Biodegradable Elastomers

ABSTRACT

The present inventions in various aspects provide elastic biodegradable polymers. In various embodiments, the polymers are formed by the reaction of a multifunctional alcohol or ether and a difunctional or higher order acid to form a pre-polymer, which is cross-linked to form the elastic biodegradable polymer. In preferred embodiments, the cross-linking is performed by functionalization of one or more OR groups on the pre-polymer backbone with vinyl, followed by photopolymerization to form the elastic biodegradable polymer composition or material. Preferably, acrylate is used to add one or more vinyls to the backbone of the pre-polymer to form an acrylated pre-polymer. In various embodiments, acrylated pre-polymers are co-polymerized with one or more acrylated co-polymers.

CROSS-REFERENCE TO RELATED APPLICATIONS

The application is a continuation of pending application, U.S. Ser. No.13/428,869, filed Mar. 23, 2012, which is a continuation of U.S. Ser.No. 11/623,041, filed Jan. 12, 2007, now U.S. Pat. No. 8,143,042, issuedMar. 27, 2012, which claims the benefit of and priority to United Statesprovisional application No. 60/758,973 filed Jan. 12, 2006 and U.S. Ser.No. 60/803,223 filed May 25, 2006.

GOVERNMENT SUPPORT

The invention was made with government support under grant numbers DE013023 awarded by the National Institute of Health and NIRT 0609182awarded by the National Science Foundation. The government has certainrights in the invention.

BACKGROUND

Biodegradable polymers are essential materials for a wide variety ofbiomedical applications including tissue engineering where cell seededconstructs are designed to replace damaged or diseased tissue. Theseconstructs often must provide stability and structural integrity withina mechanically dynamic environment without irritation to the host.Consequently, there is a considerable need and interest in developingtough biodegradable elastomers which exhibit mechanical propertiessimilar to those of soft tissue. Common biodegradable elastomersinclude, poly(glycerol sebacate), poly(citric diol),star-poly(ε-caprolactone-co-D,L-lactide), poly(tri-methylenecarbonate-co-ε-caprolactone) and poly (tri-methylenecarbonate-co-D,L-lactide).

These elastomers, however, have mechanical properties, e.g., asreflected in their elongation % and Young's modulus, that can renderthem insufficient for many biomedical applications if theirbiodegradability is to be maintained. For example, as mechanicalstrength is often proportional to polymer crosslink density, whereasdegradability is often inversely proportional to crosslink density,providing a material with both acceptable mechanical strength anddegradability is difficult.

Further, these biodegradable elastomers often must be cured at hightemperatures in vacuo for extended periods of time (e.g., 24 h) toproduce materials with acceptable mechanical properties. This, however,can preclude their use in applications where incorporation of atemperature sensitive component, e.g., a drug, growth factors, cells,etc. is desired. In addition, polymer transitions through a melt phaseupon high temperature curing and can produce bubbles which limit thecomplexity of shapes that can be achieved.

SUMMARY OF THE INVENTION

In various aspects, the present inventions provide elastomeric polymercompositions and methods for their formation and use. In variousaspects, the present inventions provide implants and methods of makingsuch implants using various embodiments of the elastomeric polymercompositions of the present inventions. Further aspects and uses of thepresent inventions are described below.

The compositions and materials of the present inventions provide abiodegradable elastomer, which, in various embodiments, has in vitro andin vivo biocompatibility. In addition, in various embodiments thepresent inventions provide provided methods for adjusting the physicaland chemical properties of the resultant composition, and thus theability to “tailor” a composition. Compositions. For example, in variousembodiments and compositions, e.g., one or more of the tensile strength,degradation and swelling properties of the elastomers can be adjusted byvarying the density of acrylate moieties in the matrix of the polymer,by incorporation of a hydrogel both.

In various embodiments, the compositions and materials of the presentinventions can be formed from a relatively inexpensive biodegradablephotocurable elastomer, poly(glycerol sebacate apidicate) PGSA. Invarious embodiments, the compositions and materials of the presentinventions can be formed in seconds via photopolymerization,facilitating, e.g., their formation in situ. In various embodiments,compositions and materials of the present inventions are formed fromviscous liquid acrylated pre-polymer, facilitating the molding and/orinjection of the acrylated pre-polymer to form materials, structures andvarious devices. In addition, in various embodiments, the photoinitiatedcrosslinking reaction used to form the compositions and materials of thepresent invention, does not require a solvent.

In various aspects, the present inventions provide elastomericcompositions comprising a cross-linked polyester; the cross-linkedpolyester comprising a polymeric unit of the general formula(-A-B—)_(n), where, n represents an integer greater than 1, A representsa substituted or unsubstituted ester and B represents a substituted orunsubstituted acid ester comprising at least two acid esterfunctionalities. At least a portion of the cross-links between polymericunits forming a dioic acid ester between the A components.

Referring to FIG. 1, various embodiments of an elastomeric composition awhich comprises a repeating polymeric unit of the general formula(-A-B—)_(n) are illustrated; the A component including a substituted orunsubstituted ester (102), the B component including a substituted orunsubstituted acid ester comprising at least two acid esterfunctionalities (104), and the cross-link forming a dioic acid ester(106) between at least a portion of the A components (102).

In various embodiments, these elastomeric compositions comprise aportion that can be represented by the general formula (I) below, wherem, n, p, q, and v are each independently integers greater than 1.

In various preferred embodiments, an elastomeric composition representedby general formula (I) is derived from cross-linking poly(glycerolsebacate)-acrylate (PGSA) using UV excitation in the presence of aphotoiniator (or other free radical initiated systems) of the acrylateto initiate the cross-linking reaction. In various embodiments of themethods of the present invention, one or more hydrogel or otherpolymeric precursors (e.g., precursors that may be modified to containacrylate groups such as poly(ethylene glycol), dextran, chitosan,hyaluronic acid, alginate, other acrylate based presursors including,for example, acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, methylacrylate, ethyl acrylate, acrylonitrile, n-butanol, methyl methacrylate,and TMPTA, trimethylol propane trimethacrylate, pentaerythritoltrimethacrylate, pentaerythritol tetramethacrylate, ethylene glycoldimethacrylate. dipentaerythritol penta acrylate, Bis-GMA (Bis phenol Aglycidal methacrylate) and TEGDMA (tri-ethylene, glycol dimethacrylate),sucrose acrylate, and combinations thereof, can be reacted with theacrylated pre-polymer (e.g., PGSA) prior to or during free radicalpolymerization to modify the cross-links between the polymer chains.

In various aspects, the present inventions provide elastomericcompositions comprising a cross-linked polyester; the cross-linkedpolyester comprising a polymeric unit of the general formula(-A-B—)_(n), cross-linked between at least a portion of the A componentsof the polyester, the cross-link forming a link comprising at least aportion of the general formula -(D)_(k)-C—; where A represents asubstituted or unsubstituted ester, B represents a substituted orunsubstituted acid ester comprising at least two acid esterfunctionalities; C represents a substituted or unsubstituted dioic acidester; D represents one or more of a substituted or unsubstituted ester,and k is an integer greater than 0 and and n an integer greater than 1.It is to be understood that the elastomeric compositions can contain oneor more kinds of cross-links in addition to a cross-link comprising adioic acid ester and an ester.

Referring to FIG. 2, various embodiments of an elastomeric compositioncomprising a repeating polymeric unit of the general formula (-A-B—)_(n)are illustrated; the A component including a substituted orunsubstituted ester (202), the B component including a substituted orunsubstituted acid ester comprising at least two acid esterfunctionalities (204), and the cross-link forming a substituted orunsubstituted dioic acid ester (206) and a substituted or unsubstitutedester (208) between at least a portion of the A components (202). Invarious embodiments, the ester linkage forms a polyester, e.g., p inFIG. 2 is an integer greater than 1.

In various embodiments, these elastomeric compositions comprise aportion that can be represented by the general formula (II) below, wherek, m, n, p, q, and v are each independently an integer greater than 1.

In various preferred embodiments, an elastomeric composition representedby general formula (II) is derived from copolymerization of PGSA withvarious proportions of an acrylated polyester, e.g., PEGD, to form oneor more crosslinks of the general formula -(D)_(k)-C—; where Crepresents a dioic acid ester, D represents an ester, and k an integergreater than 1, between polymer chains. In various embodiments, byselecting the proportion of PEGD to PGSA the material properties of theelastomeric composition can be selected. For example, in variousembodiments, the PGSA-PEG composition can provide a hydrogel material(e.g., equilibrium water content greater than about 30%) with elasticproperties.

In various embodiments, the present inventions provide an elastomericbiodegradable material formed from a cross-linked polyester, theelastomeric biodegradable material having a degradation rate that issubstantially non-monotonic as a function of overall cross-link density.In various embodiments the degradation rate is the in vitro degradationrate in phosphate buffer saline (PBS), or in acidic or alkalineconditions. In various embodiments the degradation rate is the in vivodegradation rate. In various embodiments, the present inventions providean elastomeric biodegradable material formed from a cross-linkedpolyester, the elastomeric biodegradable material having a degradationrate that is capable of being increased by increasing overall cross-linkdensity. In various embodiments, the present inventions provide anelastomeric biodegradable material formed from a cross-linked polyester,the elastomeric biodegradable material having a degradation rate that iscapable of being increased without substantially decreasing the tensileYoung's modulus of the material.

In various aspects, the present inventions provide methods for forming abiodegradable elastomeric material, comprising the steps of: (a)reacting a first component comprising two or more functionalities of thegeneral formula —OR, where R of each group is independently hydrogen oralkyl, with a second component comprising two or more acid esterfunctionalities to form a mixture of pre-polymers having a molecularweight in the range between about 300 Da and about 75,000 Da; (b)reacting the mixture of pre-polymers with an acrylate to form a mixtureof acrylated pre-polymers; and (c) irradiating the acrylated pre-polymermixture with ultraviolet light to cross-link at least a portion of theacrylated pre-polymers and form a biodegradable elastomeric material;wherein the pre-polymer mixture is not heated above about 45° C. duringirradiation, and preferably not above about 37° C., and more preferablynot above about 25° C.

In various embodiments, the methods comprise adding one or moreadditional acrylated molecules (referred to as acrylated co-polymersherein) during the reacting the mixture of pre-polymers with anacrylate, or to the mixture of acrylated pre-polymers. A wide variety ofco-polymers can be used including, but not limited to, dextran,hyaluronic acid, chitosan, and poly(ethylene glycol).

In various aspects, the present inventions provide methods for forming abiodegradable elastomeric material, comprising the steps of: (a)providing a solution comprising: a pre-polymer comprising (i) a firstcomponent comprising two or more functionalities of the general formula—OR, where R of each group is independently hydrogen or alkyl; and (ii)a second component comprising two or more acid ester functionalities;and (c) crosslinking at least a protion of the pre-polymers using one ormore of a Mitsunobu-type reaction, polymerization using a thermalinitiator, redox-pair initiated polymerization, and a Michael-typeaddition reaction using a bifunctional sulfhydryl compound.

The compositions and materials of the present inventions are suitablefor a wide range of uses. In various embodiments, the chemical andmechanical properties of these materials and compositions (and theability to adjust them) make them attractive candidates for elastomerscould find utility for treating cardiovascular disease, for bridgingneural defects where existing graft materials have severe limitations.

For example, it has been reported that the peripheral nerve has aYoung's modulus of approximately 0.45 MPa and the thoracic aorta has aYoung's modulus of 0.53 MPa. In various embodiments, the presentinvention provides compositions and materials that can achievemechanical compliance with such biological structures. In addition, invarious embodiments, the present inventions provide compositions andmaterials where, e.g., the swelling and/or degradation of thecomposition or material can be adjusted without substantially changingthe Young's modulus.

Various embodiments of the compositions and materials of the presentinventions, can be used in a variety of medical applications, including,but not limited to, bioactive agent delivery vehicles (e.g., delivery ofantibiotics, drugs, etc), patches for diabetic ulcers, abdominal implantto prevent adhesions, biodegradable adhesive, in vivo and in vitrosensors, catheters, surgical glue, cardiac, bile-duct, intestinal stent,coatings for metals, microfabrication applications (e.g., capillarynetworks), long-term circulating particles for applications includingtargeted drug delivery, blood substitutes etc., injectable drug deliverysystem for mechanically taxing environments (e.g., within joints) where,for example, the material can be configured to release drugs incontrolled manner without being compromised by a dynamic or staticexternal environment, degradable 0-rings, septums etc.

Various embodiments of the compositions and materials of the present,can be used in a variety of non-medical applications, including, but notlimited to, an absorbent garments, (e.g., disposable diapers,incontinence protectors, panty liners, sanitary napkins, etc.), chewinggum (e.g., to deliver nutrients), inflatable balloons, fishing lures,fishing flies, disposable bags, edible films (e.g., films that protectthe freshness of food product but that are biodegradable within thedigestive tract), degradable films (alternative to saranwrap/cellophane), general packaging (e.g., degradable in composts orlandfills), flavor and aroma barriers, food containers, degradable foamsfor packaging applications, degradable filters, hair products (e.g., asalternatives to existing wax products), agricultural seeding strips andtapes, cosmetics, preservation of materials (e.g. wood), limited and/orone time-use CDs, DVDs etc. (e.g., that can be written but not copied).

In various embodiments, the present inventions provide an elasticbiodegradable material formed from a cross-linked polyester compositionof the present inventions, wherein the elastic biodegradable material isin the form of a particle, tube, sphere, strand, coiled strand,capillary network, film, fiber, mesh, or sheet.

In various embodiments, the present inventions provide medical deviceformed from an elastic biodegradable material of the present inventions.In various embodiments, the medical device provides delivery of abioactive agent over time. In various embodiments, the medical device isimplanted and/or formed in situ. For example, in various embodiments,the medical device is formed by injecting an acrylated pre-polymer ofthe present inventions at a site where the medical device is desired;and irradiating the injected acrylated pre-polymer with ultravioletlight to form the medical device. In various embodiments, the medicaldevice comprises a graft and/or implant to facilitate tissue repairand/or regeneration.

In various embodiments, is provided an elastomeric biodegradablematerial formed from a cross-linked polyester of the present inventions,where the material comprises one or more of a growth factor, celladhesion sequence, polynucleotide, polysaccharide, polypeptide, anextracellular matrix component, and combinations thereof. In variousembodiments, is provided an elastomeric biodegradable material formedfrom a cross-linked polyester of the present inventions, where thematerial is seeded with one or more connective tissue cells, organcells, muscle cells, nerve cells, and combinations thereof. In variousembodiments, is provided an elastomeric biodegradable material formedfrom a cross-linked polyester of the present inventions, where thematerial is seeded with one or more tenocytes, fibroblasts, ligamentcells, endothelial cells, lung cells, epithelial cells, smooth musclecells, cardiac muscle cells, skeletal muscle cells, islet cells, nervecells, hepatocytes, kidney cells, bladder cells, urothelial cells,chondrocytes, and bone-forming cells.

The foregoing and other aspects, embodiments, and features of thepresent inventions can be more fully understood from the followingdescription and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates various embodiments of an elastomericcomposition of the present inventions.

FIG. 2 schematically illustrates various embodiments of an elastomericcomposition of the present inventions.

FIGS. 3A-D schematically illustrates a formation scheme for anelastomeric composition or material according to various embodiments ofthe present inventions. FIG. 3A illustrating polycondensation ofglycerol and sebacic acid, to form a pre-polymer (a low molecular weightpolymer is illustrated), where R is H, and alkyl, alkenyl, or alkynyl).FIG. 3B illustrating functionalization of the pre-polymer backbone witha vinyl group, here acrylation is shown. FIGS. 3C and 3D schematicallyillustrate examples of portions of the polymer network formed in avarious embodiments of a cross-linked polymer of PGSA

FIG. 4 schematically illustrates an example of the portion of thepolymer network formed in a various embodiments of a cross-linkedpolymer of PGSA-PEG.

FIG. 5A-B schematically depicts the adjustment of the physicalproperties of a polymer based on the proportion of PGSA. FIG. 5Aillustrating adjustments for a PGSA-PEG and FIG. 5B for a PGSA-Dextranco-polymer.

FIG. 6A-C schematically illustrates a formation scheme for anelastomeric composition or material according to various embodiments ofthe present inventions.

FIG. 7A-D illustrates that the elastomeric compoistions of variousembodiments of the present invention can be fabricated into a widevariety of shapes and morphologies including: (FIG. 7A)nano/microparticles; (FIG. 7B) tubes, (FIG. 7C) micropatterns, and (FIG.7D) scaffolds.

FIGS. 8A and 8B show ¹H-NMR spectra; FIG. 8A showing a spectrum of PGSpre-polymer and FIG. 8B of PGSA.

FIGS. 9A and 9B compare ATR-FTIR spectra of: PGS pre-polymer PGSpre-polymer (902); PGSA with a DA of 0.20 (904); PGSA (DA=0.54) (906);thermally cured PGS (908); photocured PGSA (DA=0.20) (910); andphotocured PGSA (DA=0.54) (912).

FIG. 10 is a plot of the degree acrylation of the PGSA versus the molesof acryloyl chloride added to the pre-polymer per mole ofglycerol-sebacate (−).

FIGS. 11A-C present data on various properties for various degrees ofacrylation (DA) of the photocured PGSA of Example 1; where FIG. 11Apresents data on the tensile strength and elongation, FIG. 11B presentsdata on Young's modulus and ultimate strength; and FIG. 11C presentsdata on swelling in ethanol, selling in water, and sol content.

FIG. 12 presents data on Young's modulus, ultimate strength, elongation% and swelling % for various weight percentages of PGSA in PEGD, forcopolymerization of PGSA (DA=0.34) and PEG diacrylate (Mw=700 Da) wherePEG chains become incorporated as crosslinks between PGSA.

FIG. 13 presents data on the in vitro degradation of PGS (filled diamondsymbols), photocured PGSA (DA=0.31, 0.54) (open square symbols forDA=0.31, open diamond sybols for DA=0.54) and PGSA (DA=0.34+5% PEGdiacrylate) (“x” symbols) in NaOH (0.1 mM) for 0, 1.5, 3, 4.5, and 6hours at 37° C. (standard deviation was smaller than 5% of mean).

FIGS. 14A-C present in vitro cell attachment and degradation data; FIGS.14A and 14B are SEM pictures of the surface of photocured PGSA (DA=0.31)(PGSA-LA) after 3 hours in 0.1 mM NaOH at 37° C., and after 12 days,respectively. FIG. 14C is a plot of cell density over time on photocuredPGSA surfaces.

FIG. 15 presents data on the enzymatic degradation by cholesterolesterase (pH 7.2, 37° C.)(n=3) as further described in Example 2.

FIGS. 16A-D present data, as further described in Example 2, comparing:FIG. 16A changes in mass; FIG. 16B water content; FIG. 16C sol content;FIG. 16D size of PGS, PGSA-LA, PGSA-HA, PGSA-PEG implants after in vivodegradation. PGS and PGSA-LA were fully degraded at implantation siteafter, respectively, 7 and 12 weeks in vivo (n=4).

FIG. 17 presents data, as further described in Example 2, on the changesin mechanical strength of PGS, PGSA-LA, PGSA-HA and PGSA-PEG during invivo degradation (n=4).

FIGS. 18A-H present SEM cross-sectional images of polymeric discs, asfurther described in Example 2, of: (FIGS. 18A and E) PGS at 3 and 5weeks in vivo, (FIGS. 18B and F) PGSA-LA at 3 and 9 weeks in vivo,(FIGS. 18C and G) PGSA-HA at 3 and 11 weeks in vivo and (FIGS. 18D andH) PGSA-PEG at 3 and 9 weeks in vivo (n=4).

FIGS. 19A-D present surface SEM images of polymeric discs, as furtherdescribed in Example 2, of: (FIG. 19A) PGS at 5 weeks in vivo, (FIG.19B) PGSA-LA at 6 weeks in vivo, (FIG. 19C) PGSA-HA at 5 weeks in vivoand (FIG. 19D) PGSA-PEG at 6 weeks in vivo (n=4).

FIGS. 20A-F present photomicrographs (400×) of H&E sections of tissueadjacent elastomeric implants, as further described in Example 2, of thetissue reaction of: (FIGS. 20A and C) PGS (positive control) after 1, 3and 5 weeks in vivo and (FIGS. 20D-F) PGSA-HA after 1, 3 and 11 weeks invivo (n=4). Arrows indicate polymer-tissue interface surface.

FIGS. 21A-F present photomicrographs (400×), and in figure inset (50×)of H&E sections of tissue adjacent elastomeric implants, as furtherdescribed in Example 2, of the tissue reaction of: (FIGS. 21A-C) PGS-LAafter 3, 6 and 6 weeks in vivo and (FIGS. 21D-F) PGSA-HA after 3, 6 and9 weeks in vivo (n=4). Arrows indicate polymer-tissue interface surface.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

Prior to further describing the present inventions, it may be helpful toprovide an understanding thereof to set forth the meanings of certainterms to be used herein.

As used herein, the article “a” is used in its indefinite sense to mean“one or more” or “at least one.” That is, reference to any element ofthe present teachings by the indefinite article “a” does not exclude thepossibility that more than one of the element is present.

The term “biomolecules”, as used herein, refers to molecules (e.g.,proteins, amino acids, peptides, polynucleotides, nucleotides,carbohydrates, sugars, lipids, nucleoproteins, glycoproteins,lipoproteins, steroids, etc.) whether naturally-occurring orartificially created (e.g., by synthetic or recombinant methods) thatare commonly found in cells and tissues. Specific classes ofbiomolecules include, but are not limited to, enzymes, receptors,neurotransmitters, hormones, cytokines, cell response modifiers such asgrowth factors and chemotactic factors, antibodies, vaccines, haptens,toxins, interferons, ribozymes, anti-sense agents, plasmids, DNA, andRNA.

The term “biocompatible”, as used herein is intended to describematerials that do not elicit a substantial detrimental response in vivo.

As used herein, “biodegradable” polymers are polymers that degrade downto monomeric species under physiological or endosomal conditions. Invarious preferred embodiments, the polymers and polymer biodegradationbyproducts are biocompatible. Biodegradable polymers are not necessarilyhydrolytically degradable and may require enzymatic action to fullydegrade.

The phrase “physiological conditions”, as used herein, relates to therange of chemical (e.g., pH, ionic strength) and biochemical (e.g.,enzyme concentrations) conditions likely to be encountered in theintracellular and extracellular fluids of tissues. For most tissues, thephysiological pH ranges from about 7.0 to 7.4.

The terms “polynucleotide”, “nucleic acid”, or “oligonucleotide” referto a polymer of nucleotides. The terms “polynucleotide”, “nucleic acid”,and “oligonucleotide”, may be used interchangeably. Typically, apolynucleotide comprises at least three nucleotides. DNAs and RNAs arepolynucleotides. The polymer may include natural nucleosides (i.e.,adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine,deoxythymidine, deoxyguanosine, and deoxycytidine), nucleoside analogs(e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine,3-methyl adenosine, C5-propynylcytidine, C5-propynyluridine,C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-methylcytidine,7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine,O(6)-methylguanine, and 2-thiocytidine), chemically modified bases,biologically modified bases (e.g., methylated bases), intercalatedbases, modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose,arabinose, and hexose), or modified phosphate groups (e.g.,phosphorothioates and 5′-N-phosphoramidite linkages).

As used herein, a “polypeptide”, “peptide”, or “protein” comprises astring of at least three amino acids linked together by peptide bonds.The terms “polypeptide”, “peptide”, and “protein”, may be usedinterchangeably. Peptide may refer to an individual peptide or acollection of peptides. Inventive peptides preferably contain onlynatural amino acids, although non-natural amino acids (i.e., compoundsthat do not occur in nature but that can be incorporated into apolypeptide chain; see, for example,http://www.cco.caltech.edu/˜dadgrp/Unnatstruct.gif, which displaysstructures of non-natural amino acids that have been successfullyincorporated into functional ion channels) and/or amino acid analogs asare known in the art may alternatively be employed. Also, one or more ofthe amino acids in an inventive peptide may be modified, for example, bythe addition of a chemical entity such as a carbohydrate group, aphosphate group, a farnesyl group, an isofarnesyl group, a fatty acidgroup, a linker for conjugation, functionalization, or othermodification, etc. In a preferred embodiment, the modifications of thepeptide lead to a more stable peptide (e.g., greater half-life in vivo).These modifications may include cyclization of the peptide, theincorporation of D-amino acids, etc. None of the modifications shouldsubstantially interfere with the desired biological activity of thepeptide.

The terms “polysaccharide”, “carbohydrate”, or “oligosaccharide” referto a polymer of sugars. The terms “polysaccharide”, “carbohydrate”, and“oligosaccharide”, may be used interchangeably. Typically, apolysaccharide comprises at least three sugars. The polymer may includenatural sugars (e.g., glucose, fructose, galactose, mannose, arabinose,ribose, and xylose) and/or modified sugars (e.g., 2′-fluororibose,2′-deoxyribose, and hexose).

As used herein, “bioactive agents” is used to refer to compounds orentities that alter, inhibit, activate, or otherwise affect biologicalor chemical events. For example, bioactive agents may include, but arenot limited to, anti-AIDS substances, anti-cancer substances,antibiotics, immunosuppressants, anti-viral substances, enzymeinhibitors, neurotoxins, opioids, hypnotics, anti-histamines,lubricants, tranquilizers, anti-convulsants, muscle relaxants andanti-Parkinson substances, anti-spasmodics and muscle contractantsincluding channel blockers, miotics and anti-cholinergics, anti-glaucomacompounds, anti-parasite and/or anti-protozoal compounds, modulators ofcell-extracellular matrix interactions including cell growth inhibitorsand anti-adhesion molecules, vasodilating agents, inhibitors of DNA, RNAor protein synthesis, anti-hypertensives, analgesics, anti-pyretics,steroidal and non-steroidal anti-inflammatory agents, anti-angiogenicfactors, anti-secretory factors, anticoagulants and/or antithromboticagents, local anesthetics, ophthalmics, prostaglandins,anti-depressants, anti-psychotic substances, anti-emetics, and imagingagents. In certain embodiments, the bioactive agent is a drug.

A more complete listing of examples of bioactive agents and specificdrugs suitable for use in the present invention may be found in“Pharmaceutical Substances: Syntheses, patents, applications” by AxelKleemann and Jurgen Engel, Thieme Medical Publishing, 1999; the “MerckIndex: An Encyclopedia of Chemicals, Drugs, and Biologicals”, Edited bySusan Budavari et al., CRC Press, 1996, and the United StatesPharmacopeia-25/National Formulary-20, published by the United StatesPharmcopeial Convention, Inc., Rockville Md., 2001, the entire contentsof which are herein incorporated by reference.

As used herein, the term “tissue” refers to a collection of similarcells combined to perform a specific function, and any extracellularmatrix surrounding the cells.

The term “substituted” is intended to describe groups havingsubstituents replacing a hydrogen on one or more atoms, e.g., carbon,nitrogen, oxygen, etc., of a molecule. Substituents can include, forexample, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkoxyl, cyano, amino(including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic group. Accordingly, thephrase “a substituent as described herein” or the like refers to one ormore of the above substituents, and combinations thereof.

The term “alkyl” includes saturated aliphatic groups, which includesboth “unsubstituted alkyls” and “substituted alkyls”, the latter ofwhich refers to alkyl groups having substituents replacing a hydrogen onone or more carbons of the hydrocarbon backbone. The term “alkyl”includes straight-chain alkyl groups (e.g., methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chainalkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl(alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl), and cycloalkyl substituted alkyl groups. The term “alkyl”also includes the side chains of natural and unnatural amino acids.

An “alkylaryl” or an “aralkyl” group is an alkyl substituted with anaryl (e.g., phenylmethyl (benzyl)).

The term “aryl” includes 5- and 6-membered single-ring aromatic groups,as well as multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g.,naphthalene, anthracene, phenanthrene, etc.). The aromatic ring(s) canbe substituted at one or more ring positions with such substituents asdescribed above. Aryl groups can also be fused or bridged with, e.g.,alicyclic or heterocyclic rings which are not aromatic so as to form,e.g., a polycycle.

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one double bond. For example, the term “alkenyl”includes straight-chain alkenyl groups (e.g., ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.),branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups(cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, andcycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenylincludes both “unsubstituted alkenyls” and “substituted alkenyls”, thelatter of which refers to alkenyl groups having substituents replacing ahydrogen on one or more carbons of the hydrocarbon backbone.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond. For example, the term “alkynyl”includes straight-chain alkynyl groups (e.g., ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.),branched-chain alkynyl groups, and cycloalkyl or cycloalkenylsubstituted alkynyl groups. The term alkynyl includes both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl groups having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone.

The term “acyl” includes compounds and groups which contain the acylradical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl groups having substituents replacing a one or more of thehydrogen atoms.

The term “acylamino” includes groups wherein an acyl group is bonded toan amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “aroyl” includes compounds and groups with an aryl orheteroaromatic group bound to a carbonyl group. Examples of aroyl groupsinclude phenylcarboxy, naphthyl carboxy, etc.

The terms “alkoxyalkyl”, “alkylaminoalkyl” and “thioalkoxyalkyl” includealkyl groups, as described above, which further include oxygen, nitrogenor sulfur atoms replacing one or more carbons of the hydrocarbonbackbone, e.g., oxygen, nitrogen or sulfur atoms.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups and may include cyclic groups such as cyclopentoxy.

The term “amine” or “amino” includes compounds where a nitrogen atom iscovalently bonded to at least one carbon or heteroatom. The term “alkylamino” includes groups and compounds wherein the nitrogen is bound to atleast one additional alkyl group. The term “dialkyl amino” includesgroups wherein the nitrogen atom is bound to at least two additionalalkyl groups. The term “arylamino” and “diarylamino” include groupswherein the nitrogen is bound to at least one or two aryl groups,respectively. The term “alkylarylamino,” “alkylaminoaryl” or“arylaminoalkyl” refers to an amino group that is bound to at least onealkyl group and at least one aryl group. The term “alkaminoalkyl” refersto an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom that isalso bound to an alkyl group.

The term “amide” or “aminocarboxy” includes compounds or groups thatcontain a nitrogen atom that is bound to the carbon of a carbonyl or athiocarbonyl group. The term includes “alkaminocarboxy” groups thatinclude alkyl, alkenyl, or alkynyl groups bound to an amino group boundto a carboxy group. It includes arylaminocarboxy groups that includearyl or heteroaryl groups bound to an amino group which is bound to thecarbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarboxy,” “alkenylaminocarboxy,” “alkynylaminocarboxy,” and“arylaminocarboxy” include groups wherein alkyl, alkenyl, alkynyl andaryl groups, respectively, are bound to a nitrogen atom which is in turnbound to the carbon of a carbonyl group.

The term “carbonyl” or “carboxy” includes compounds and groups whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of groups that contain a carbonylinclude aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc. The term “carboxy group” or “carbonyl group” refers togroups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl group. For example, the term includes groups such as,for example, aminocarbonyl groups, (wherein a nitrogen atom is bound tothe carbon of the carbonyl group, e.g., an amide), aminocarbonyloxygroups, wherein an oxygen and a nitrogen atom are both bond to thecarbon of the carbonyl group (e.g., also referred to as a “carbamate”).Furthermore, aminocarbonylamino groups (e.g., ureas) are also include aswell as other combinations of carbonyl groups bound to heteroatoms(e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms).Furthermore, the heteroatom can be further substituted with one or morealkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. groups.

The term “ether” includes compounds or groups that contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom that is covalentlybonded to another alkyl group.

The term “ester” includes compounds and groups that contain a carbon ora heteroatom bound to an oxygen atom that is bonded to the carbon of acarbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a group wherein allhydrogens are replaced by halogen atoms.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, and oxygen. The term“heterocycle” or “heterocyclic” includes saturated, unsaturated,aromatic (“heteroaryls” or “heteroaromatic”) and polycyclic rings whichcontain one or more heteroatoms. The heterocyclic may be substituted orunsubstituted. Examples of heterocyclics include, for example,benzodioxazole, benzofuran, benzoimidazole, benzothiazole,benzothiophene, benzoxazole, chromene, deazapurine, furan, indole,indolizine, imidazole, isoxazole, isoindole, isoquinoline, isothiaozole,methylenedioxyphenyl, napthridine, oxazole, purine, pyran, pyrazine,pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline,tetrazole, thiazole, thiophene, and triazole. Other heterocycles includemorpholino, piprazine, piperidine, thiomorpholino, and thioazolidine.

The terms “polycyclic ring” and “polycyclic ring structure” includegroups with two or more rings (e.g., cycloalkyls, cycloalkenyls,cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbonsare common to two adjoining rings, e.g., the rings are “fused rings”.Rings that are joined through non-adjacent atoms are termed “bridged”rings. Each of the rings of the polycyclic ring can be substituted withsuch substituents as described above.

In various aspects, the present inventions provide elastic biodegradablepolymer compositions and materials formed by the reaction of amultifunctional alcohol or ether (that is a compound having two or moreOR groups, where each R is independently H and an alkyl) and adifunctional or higher order acid (e.g., a diacid) to form a pre-polymer(see, e.g., FIG. 3A), which is cross-linked to form the elasticbiodegradable polymer. In preferred embodiments, the cross-linking isperformed by functionalization of one or more OR groups on thepre-polymer backbone with vinyl (see, e.g., FIG. 3B), followed byphotopolymerization to form the elastic biodegradable polymercomposition or material. Preferably, acrylate is used to add one or morevinyls to the backbone of the pre-polymer to form an acrylatedpre-polymer.

Referring to FIGS. 3A-D and 4, this formation scheme is schematicallyillustrated. It is to be understood that the acrylation andpolymerization reactions can result in several types of cross-linkswithin the polymer network. For example, the acrylated hydroxyl uponphotopolymerization can yield acid ester cross-links to an alkyl chain(also know in the art as a methylene chain) (see, e.g., FIG. 3C), aswell as dioic acid ester cross-links when, for example, two acrylatedhydroxides react (see, e.g., FIG. 3D.)

Diacid Component

A wide variety of diacid, or higher order acids, can be used in theformation of a elastic biodegradable polymer compositions and materialsaccording to various embodiments of the present invention, including,but are not limited to, glutaric acid (5 carbons), adipic acid (6carbons), pimelic acid (7 carbons), suberic acid (8 carbons), andazelaic acid (nine carbons). Exemplary long chain diacids includediacids having more than 10, more than 15, more than 20, and more than25 carbon atoms. Non-aliphatic diacids can be used. For example,versions of the above diacids having one or more double bonds can beemployed to produce glycerol-diacid co-polymers. Amines and aromaticgroups can be incorporated into the carbon chain. Exemplary aromaticdiacids include terephthalic acid and carboxyphenoxypropane. The diacidscan also include substituents as well. For example, in variousembodiments, reactive groups like amine and hydroxyl can be usedincrease the number of sites available for cross-linking. In variousembodiments, amino acids and other biomolecules can be used to modifythe biological properties of the polymer. In various embodiments,aromatic groups, aliphatic groups, and halogen atoms can be used tomodify the inter-chain interactions within the polymer.

Pre-Polymer

In various embodiments, the pre-polymer of the present inventionscomprises a diol, or higher order, portion and a diacid, or higher orderacid, portion. In various embodiments, the pre-polymer can includeunsaturated diols, e.g., tetradeca-2,12-diene-1,14-diol, or other diolsincluding macromonomer diols such as, e.g., polyethylene oxide, andN-methyldiethanoamine (MDEA). In addition to incorporating these intothe pre-polymer, the diols can be incorporated into the resultantcross-linked polymer through, e.g., acrylate chemistry. For example, thediols could be first acrylated and then combined with acrylatedpre-polymer using a free radical polymerization reaction. In variousembodiments, aldehydes and thiols can be used, e.g., for attachingproteins and growth factors to the pre-polymer.

Vinyl Addition to Pre-Polymer

A variety of techniques can be used to functionalize the pre-polymerwith vinyl. In various preferred embodiment an acrylate, such as, forexample, an acrylate monomer. Examples of suitable acrylate monomersinclude, but are not limited to, methacrylate, vinyl methacrylate,maleic methacrylate, and those having the structure

where R₁ can be methyl or hydrogen; and R₂, R₂′, and R₂″ can be alkyl,aryl, heterocycles, cycloalkyl, aromatic heterocycles, multicycloalkyl,hydroxyl, ester, ether, halide, carboxylic acid, amino, alkylamino,dialkylamino, trialkylamino, amido, carbamoyl thioether, thiol, alkoxy,or ureido groups. R₂, R₂′, and R₂″ may also include branches orsubstituents including alkyl, aryl, heterocycles, cycloalkyl, aromaticheterocycles, multicycloalkyl, hydroxyl, ester, ether, halide,carboxylic acid, amino, alkylamino, dialkylamino, trialkylamino, amido,carbamoyl, thioether, thiol, alkoxy, or ureido groups. Further examplesof suitable acrylate monomers include, but are not limited to,

In addition to acrylate monomers, other agents can be used to form afunctionalized pre-polymer that can be cross-linked byphotopolymerization in accordance with various embodiments of thepresent inventions. Examples of such agents include, but are not limitedto, glycidyl, epichlorohydrin, triphenylphosphine, diethylazodicarboxylate (DEAD), divinyladipate, and divinylsebacate with theuse of enzymes as catalysts, phosgene-type reagents, di-acid chlorides,bis-anhydrides, bis-halides, metal surfaces, and combinations thereof.

It is to be understood that, in various embodiments, vinyl groups can beincorporated in the backbone of the pre-polymer using, e.g., freecarboxyl groups on the pre-polymer. For example, hydroxyethylmethacrylate can be incorporated through the COOH groups of thepre-polymer using carbonyl diimidazole activation chemistry.

Vinyl groups can be incorporated in the backbone of the pre-polymer withor with-out the use of catalyst, although the use of a catalyst ispreferred. A wide variety of catalysts can be used in variousembodiments, including, but not limited to, 4-(dimethylamino)pyridine,N-hydroxy succinimide, carbodiimides, and pyridine. Preferably, thereaction is carried out in a solvent, examples of suitable solventsinclude, but are not limited to, benzene, toluene, chloroform,dichloromethane, ethyl acetate, and tethrahydrofuran.

In various embodiments, acrylation of the pre-polymer can be carried outby reacting the pre-polymer with acryloyl chloride (in the presence oftriethylamine and 4-(dimethylamino)pyridine (4-DMAP) as catalysts) inanhydrous dichloromethane. Using these reagents it is preferred thatthat this reaction is carried out under extremely dry conditions. Anexample of a resultant acrylation is schematically illustrated in FIG.3B. It is to be understood that not all binding possibilities andresultant products are shown in FIG. 3B. For example, although it isbelieved that the backbone OH groups of the pre-polymer arepreferentially acrylated, the carboxylic acid groups can also bemodified.

The degree of acrylation of the pre-polymer can be used to adjust theproperties of the resultant cross-linked polymer. Accordingly, invarious aspects the present inventions provide methods for formation ofelastomeric polymers with specific physical and mechanical properties.In various embodiments, one or more of the degree of acrylation and theuse of substituents on the acrylate groups can be used to controlproperties such as degradation and swelling and mechanical properties.

The molar ratio of acryloyl chloride to available hydroxyl groups can bevaried to adjust the degree of acrylation. In various embodiments, theacrylated pre-polymer is a viscous liquid that can be cured withoutsolvent. Accordingly, in various embodiments, the present inventionsprovide methods for in vivo curing of the acrylated pre-polymer to forma elastomeric biodegradable composition or material.

Photopolymerization and

In various embodiments, the acrylated pre-polymers into a polymericnetwork using a free radical initiated reaction, such as, for example,by photoinitiated polymerization, photopolymerization. In variouspreferred embodiments, acrylated pre-polymer is irradiated with light(typically ultraviolet (UV) light) in the presence of a photoinitiatorto facilitate the reaction. Examples of suitable photoinitiatorsinclude, but are not limited to: 2-dimethoxy-2-phenyl-acetophenone,2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure2959), 1-hydroxycyclohexyl-1-phenyl ketone (Irgacure 184),2-hydroxy-2-methyl-1-phenyl-1-propanone (Darocur 1173),2-benzyl-2-(dimehylamino)-1-[4-morpholinyl) phenyl]-1-butanone (Irgacure369), methylbenzoylformate (Darocur MBF), oxy-phenyl-aceticacid-2-[2-oxo-2-phenyl-acetoxy-ethoxy]-ethyl ester (Irgacure 754),2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone(Irgacure 907), diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide(Darocur TPO), phosphine oxide, phenyl bis(2,4,6-trimethyl benzoyl)(Irgacure 819), and combinations thereof. In various preferredembodiements, acrylated pre-polymer is irradiated with visible light(typically blue light) in the presence of a photoinitiator to facilitatethe reaction. Examples of photoinitiators for visible light includecamphorquinone among others.

In various embodiments, e.g., in vivo photopolymerization and othermedical applications, the use of cytocompatible photoinitiators ispreferred and may be require by regulatory agencies. It has beenreported that the photoinitiator Irgacure 2959 causes minimalcytotoxicity (cell death) over a broad range of mammalian cell types andspecies.

Cross-Links and the Polymer Network

It is to be understood that in the formation of a polymer network thatthe links and polymer strands of the network are not homogeneous. Forexample, FIGS. 3C and 3D schematically illustrate examples of portionsof the polymer network formed by the photopolymerization methods of thepresent invention using PGSA.

In various aspects of the present invention, the formation of differentcross-links in the polymer network is exploited to adjust, or even“tailor” the properties of the resultant polymer. For example, FIG. 4schematically illustrate examples of portions of the polymer networkformed by the photopolymerization methods of the present invention usingPGSA and PEGD, it being understood that cross-links substantially asillustrated in FIGS. 3C and 3D are also present in the PGSA-PEG polymernetwork.

In various embodiments, a biodegradable material formed from the acomposition of the present invention not containing a co-polymer, isprovided that has one or more of the following properties: (a) a tensileYoung's modulus less than about 1.5 MPa when measured according to ASTMstandard D412-98a; (b) a tensile Young's modulus greater than about 0.05MPa and an elongation of greater than about 45%, both when measuredaccording to ASTM standard D412-98a; (c) a Young's modulus in the rangebetween about 0.4 MPa and about 0.55 MPa when measured according to ASTMstandard D412-98a; (d) a maximum elongation greater than about 170%; (e)a degree of acrylation in the range between about 0.25 to about 0.35 anda Young's modulus in the range between about 0.3 and 0.5 MPa whenmeasured according to ASTM standard D412-98a; (f) a degree of acrylationin the range between about 0.35 to about 0.45 and a Young's modulus inthe range between about 0.7 and 1 MPa when measured according to ASTMstandard D412-98a; (g) a degree of acrylation in the range between about0.25 to about 0.5 and an elongation greater than about 40%.

“Co-Polymer” Networks

In various aspects, the present inventions provide elastic biodegradablepolymer compositions and materials formed from an acrylated pre-polymerof the present inventions and one or more additional molecules (referredto as co-polymers herein) functionalized to the acrylate of theacrylated pre-polymer and/or a hydroxyl group of the acrylatedpre-polymer. A wide variety of co-polymers can be used including, butnot limited to, one or more hydrogel or other polymeric precursors(e.g., precursors that may be modified to contain acrylate groups suchas poly(ethylene glycol), dextran, chitosan, hyaluronic acid, alginate,acrylate based presursors including, for example, acrylic acid, butylacrylate, 2-ethylhexyl acrylate, methyl acrylate, ethyl acrylate,acrylonitrile, n-butanol, methyl methacrylate, and TMPTA, trimethylolpropane trimethacrylate, pentaerythritol trimethacrylate,pentaerythritol tetramethacrylate, ethylene glycol dimethacrylate.dipentaerythritol penta acrylate, Bis-GMA (Bis phenol A glycidalmethacrylate) and TEGDMA (tri-ethylene, glycol dimethacrylate), sucroseacrylate, etc. and combinations thereof, can be reacted with theacrylated pre-polymer (e.g. PGSA) prior to or during free radicalpolymerization to modify the cross-links between the polymer chains.

In various aspects, the present inventions provide elastic biodegradablepolymer compositions and materials formed by the reaction of amultifunctional alcohol or ether (that is a compound having two or moreOR groups, where each R is independently H and an alkyl) and adifunctional or higher order acid (e.g., a diacid) to form a pre-polymer(see, e.g., FIG. 3A). In various embodiments, at least a portion of thepre-polymers are functionalized with a vinyl group to form a mixture ofacrylated pre-polymers which are reacted with one or more co-polymers toform. It is to be under stood that the co-polymer can be added beforeacrylation of the pre-polymer, during the acrylation reaction, after tothe acrylated pre-polymer, or a combination thereof. The resultantmixture is then photopolymerized to form the polymer network. In variouspreferred embodiments, the co-polymer is acrylated and the acrylatedco-polymer combined with the acrylated pre-polymer. In variousembodiments, the acrylation of the co-polymer and/or prepolymer with anassymetrical monoacrylate molecules (e.g. Acryloyl-poly(ethyleneglycol)-N-hydroxy succinimide) provides, for example, an anchoringmoiety that can be further modified (e.g., addition of cell-adhesivemolecules).

In various aspects of the present invention, the formation of differentcross-links in the polymer network is exploited to adjust, or even“tailor” the properties of the resultant polymer. For example, invarious embodiments two or more types of cross-links (e.g. numbers ofcarbons, different types of groups, e.g., aromatic groups being morerigid, etc.) are used to adjust the properties of the resultant polymernetwork. In various embodiments, an acrylated pre-polymer (e.g., PGSA)can be combined with a co-polymer (e.g. PEG) in proportions to provide,e.g., one or more of swelling control, degradation control andanti-fouling of the crosslinked polyester.

For example, in various embodiments, combining an acrylated pre-polymerwith other acrylated co-polymers can be used to obtain degradablematerials with properties that span rigid materials to tough degradableelastomers to soft hydrogels. FIGS. 5A and 5B schematically illustratethat range over which various chemical and physical properties can beadjusted by adjusting the ratio of the acrylated pre-polymer andco-polymer in the material. FIG. 5A illustrating the adjustments for aPGSA-PEG composition or material, and FIG. 5B illustrating theadjustments for a PGSA-Dextran. In addition, as discussed herein,further property control can be achieved by adjustment of the DA of thepre-polymer, co-polymer, or both.

In various embodiments, a liquid acrylated pre-polymer matrix iscombined with acrylated hydrogel precursors to impart mechanical,biodegradable, and swelling properties that are not normally associatedwith typical hydrogel materials (see, FIG. 12). For example, a hydrogelformed from 20% (w/w) poly(ethylene glycol) di-acrylate (PEGD, 700 Da)in water exhibits an elongation of 14%, Young's modulus of 0.54 MPa andultimate strength of 0.063 MPa. Through combining PEG with PGSA(DA=0.5), the Young's modulus, ultimate strength, elongation andswelling ratio can be precisely controlled (see, FIG. 12). Withincreasing acrylated pre-polymer concentration the elongation rangedfrom 4 to 60%, Young's modulus from 20 to 0.6 MPa and ultimate strengthfrom 0.890 to 0.270 MPa (see, FIG. 12). The networks formed by thecopolymerization of PEGD with acrylated pre-polymer (DA=0.5) (50:50)showed a ten fold higher Young's modulus and ultimate strength than thetypical PEGDA hydrogel while maintaining its elongation at break (see,FIG. 12). Increased elongation was found in materials containing greaterthen 50% PEGDA. Also, the swelling behavior of these networks can betuned from 40% to 10% through changing the concentration of acrylatedpre-polymer between 10% and 90%. PGSA elastomeric networks aredegradable at physiologic conditions and show cell-adhesive andnon-cytotoxic properties. As can be seen, the present invention invarious embodiments can provide materials and compositions where thedegradation rate can be increased without necessarily decreasing themechanical strength because, it is believed with out being held totheory, of the incorporation of two or more types of cross-links. As itcan also be seen, the present invention in various embodiments canprovide a degradation rate that is substantially independent of overallcrosslink density and/or substantially independent of overall crosslinkdensity within a range of overall crosslink densities.

In various embodiments, a biodegradable material formed from the acomposition of the present invention containing a co-polymer, isprovided that has one or more of the following properties: (a) a tensileYoung's modulus less than about 17 MPa when measured according to ASTMstandard D412-98a; (b) a tensile Young's modulus greater than about 0.5MPa when measured according to ASTM standard D412-98a; (c) a tensileYoung's modulus greater than about 0.6 MPa and an elongation of greaterthan about 20%, both when measured according to ASTM standard D412-98a;(d) a tensile Young's modulus greater than about 0.25 MPa when measuredaccording to ASTM standard D412-98a and a swelling in water of greaterthan about 1%; (e) a tensile Young's modulus greater than about 0.25 MPawhen measured according to ASTM standard D412-98a and a swelling inwater of greater than about 20%; (f) a tensile Young's modulus greaterthan about 0.25 MPa when measured according to ASTM standard D412-98aand a swelling in water of greater than about 40%; (g) a tensile Young'smodulus greater than about 0.25 MPa when measured according to ASTMstandard D412-98a and a swelling in water of greater than about 80%; (h)a Young's modulus in the range between about 0.4 MPa and about 0.55 MPawhen measured according to ASTM standard D412-98a; (i) a maximumelongation greater than about 60%; (j) a maximum elongation greater thanabout 100%; (k) a maximum elongation greater than about 160%; (1) adegree of acrylation in the range between about 0.25 to about 0.35 and aYoung's modulus in the range between about 0.6 and 1.0 MPa when measuredaccording to ASTM standard D412-98a; (m) a degree of acrylation in therange between about 0.25 to about 0.5 and an elongation greater thanabout 40%; (n) a degree of acrylation in the range between about 0.25 toabout 0.35 and a Young's modulus in the range between about 0.6 and 1.0MPa when measured according to ASTM standard D412-98a, and a crosslinkdensity in the range between about 90 and 120.

Forms and Fabrication of Various Morphologies

The liquid acrylated pre-polymers, and acrylated pre-polymer/co-polymercompositions of the present invention be processed into a wide range offormats and geometries. Referring to FIGS. 7A-D, the acrylatedpre-polymer can used to manufacture nanoparticles and/or microparticlesof the compositions and materials of the present inventions (FIG. 7A),which was previously not possible with, e.g., PGS due to the processingconditions (thermal curing). In various embodiments, such particles canbe used for the controlled release of drugs, e.g., in joints or othermechanically dynamic environments. The acrylated pre-polymer can used tomanufacture very thin walled tubes of the compositions and materials ofthe present inventions (FIG. 7B); the tube illustrated having an innerdiameter of about 1 mm and an about 0.20 mm wall thickness. In variousembodiments, such tubes cab be used, e.g., as small-diameter vasculargrafts were made. The acrylated pre-polymer can processed to providecompositions and materials of the present inventions havingmicropatterned surfaces (FIG. 7C), and porous scaffolds (FIG. 7D). Theacrylated pre-polymer can also be processed into thicker (>6 mm)geometries. For example, 20 mm thick geometries were fabricated, whichwas previously not possible with thermally cured PGS, due to bubbleformation. In various embodiments, the ability to form materials andcompositions of the present invention into thicker structures withoutsubstantial bubble formation, facilitates the formation of complexstructures.

The structures illustrated in FIGS. 7A-D, were prepared substantially asfollows, acrylated pre-polymer with 0.1% phot initiator were molded intovarious shapes. For scaffolds, the macromer solution was poured overtopa porogen (e.g. sugar, salt) followed by UV polymerization and porogenleaching in water. For micropatterned PGSA, a thin layer of acrylatedpre-polymer was replica molded on micropatterned silicon masters andphotopolymerized. For tube formation, the acrylated pre-polymer solutionwas poured into a glass mold and photocured. Nano/micro particles wereprepared from the acrylated pre-polymer using an oil-in-water emulsionsolvent evaporation procedure (single emulsion method).

Methods of Fabrication

In various aspects the present inventions provide methods of formingbiodegradable elastomeric compositions, materials and devices. Invarious embodiments, to fabricate photocurable biodegradable elastomersat room temperature, the following process can be employed. (1) apre-polymer, e.g., from glycerol and sebacic acid, is created; (2)functional hydroxyl groups on backbone of the pre-polymer are acrylatedand the reaction product subsequently purified; and (3) the acrylatedpre-polymer was is photopolymerized with UV light in the presence of aphotoinitiator. Where glycerol and sebacic acid is used to form thepre-polymer, the resultant elastomer is referred to as poly(glycerolsebacate adipate) PGSA. In various embodiments, a PGS pre-polymer had aweight average molecular weight (Mw) of 23 kDa and a molar compositionof approximately 1:1 glycerol:sebacic acid. To functionalize thepre-polymer with vinyl groups, it can be reacted with different molarratios of acryloyl chloride, at room temperature.

In various embodiments, where glycerol and sebacic acid is used to formthe pre-polymer and acrylation is by acryloyl chloride, the degree ofacrylation (DA) increases substantially linearly when the molar ratio ofacryloyl chloride to glycerol-sebacate can be varied from 0.3 to 0.8(see, e.g., FIG. 10) and increasing the DA in PGSA from 0.3-0.8, the canincrease the crosslink density, for example, from about 6 to about 185mol/m³ and the relative molecular mass between crosslinks can bedecreased.

In various aspects, to fabricate biodegradable elastomers at roomtemperature, provided are methods using one or more of a Mitsunobu-typereaction, polymerization using a thermal initiator, redox-pair initiatedpolymerization, Michael-type addition reaction using a bifunctionalsulfhydryl compound, to cross-link the pre-polymers.

In various embodiments, a Mitsunobu type reaction is used to cross-linkthe pre-polymer. For example, referring to FIG. 6A, a PGS pre-polymerdissolved in THF is reacted, at room temperature and pressureconditions, with diisopropyl azodicarboxylate and triphenylphosphine.Within about 1 hour of reaction time the final elastomeric cross-linkedpolyester composition product was formed. The mild conditions of thisreaction, for example, also permit the incorporation of a variety offunctional groups, such as, e.g., esters, epoxides, halides into theelastomeric cross-linked polyester composition.

In various embodiments, mono-acids can be used to introduce ester linkedside-chains, and mono-alcohols can be used to create ether linkedside-chains (see FIG. 6B). In various embodiments, poly-beta aminoesters, can be created, a class of biomaterials that have shown promisein gene delivery. One potential limitation in the development ofpoly-beta amino esters for clinical applications is the inability tosynthesize high molecular weight products. The application of theMisunobu-type reaction of the present inventions could be useful inovercoming this obstacle to produce high molecular weight formulationsby crosslinking side chains (see, e.g., FIG. 6C). In variousembodiments, the present inventions thus include, particles for genedelivery comprising poly-beta amino ester microspheres.

Further Uses and Applications

Due to its elastomeric nature, the compositions and materials of thepresent inventions can find application in a wide variety ofapplications including tissue engineering of tissues, especially muscletissue, artery, and heart valves.

For example, in various embodiments, a biodegradable elastomericcompositions and materials of the present can be used in the form oftubes, e.g., for peripheral nerve reconstruction. Preferably, the tubeis constructed to withstand pressure of the surrounding tissue and guidethe nerve in its outgrowth, substantially unhampered by scar tissueformation. In peripheral nerve regeneration applications, it ispreferred that the material be functionalized (e.g., with GRGD) tofacilitate the attachment and guidance of Schwann cells.

For example, in various embodiments, biodegradable elastomericcompositions and materials of the present can be used as a matrix,scaffold, or structure for cell attachment and/or encapsulation. Invarious embodiments, short-peptides (e.g., GRGD) can be incorporatedinto the photocured polymer to enhance cell adhesion. Incorporation ofthese short peptides into the photocured polymer can be achieved bymixing the functionalized peptides with the PGSA followed byphotocuring. For example, in various embodiments, a GRGD peptide can befunctionalized with a poly(ethylene glycol) spacers and an acrylategroup. In various embodiments, the surface of the material can benano-patterned, e.g., on the inside of the tube, to guide cells. Forexample, in the case of a nerve graft, the material can benano-patterned to enhance the cell guidance over the nerve graft andguide the Schwann cells.

In various embodiments, the present inventions provide biodegradableelastomeric compositions and materials as a 3D matrix for theencapsulation and proliferation of cells. In various embodiments, thesematrixes are configured for stem cells.

For example, in various embodiments a liquid porogen/cell deliveryvehicle consisting of glycerol is formed as a temporary substrate toprotect the encapsulated stem cells and to create pores within theresultant PGSA network. PGSA was mixed with glycerol followed by UVcuring and submersion into water creating a porous scaffold, whichswells in an aqueous solution up to 300%. Human embryonic stem cellsdispersed in glycerol, mixed with PGSA, UV cured and placed in cellculture media created an environment for the encapsulated cells toattach and proliferate. Specifically, within 24 hours the stem cellswere observed to have attached to the PGSA network, glycerol diffusedout of the scaffold and cell culture media diffused into the scaffold.Cell proliferation was observed up to 7 days. The porous scaffoldsshowed a minimal degradation in vitro and maintained its 3D structure upto 30 days.

The hydroxyl groups on the compositions and materials of the presentinventions provide sites to which molecules may be attached to modifythe bulk or surface properties of the material. For example, in variousembodiments, tert-butyl, benzyl, or other hydrophobic groups can beadded to the material to reduce the degradation rate. In variousembodiments, polar organic groups such as methoxy can be used tofacilitate adjustment of degradation rate and hydrophilicity. In variousembodiments, addition of hydrophilic groups, for example, sugars, atthese sites can be used to increase the degradation rate.

In various embodiments, acids can be added to the polymer to modify theproperties of the material. For example, molecules with carboxylic orphosphoric acid groups or acidic sugars can be added. In variousembodiments, charged groups such as sulfates and amines can be attachedto the polymer. Groups that are added to the polymer can be added, forexample, via linkage to a hydroxyl group (substituting for hydrogen),linked directly to the polymer backbone by substituting for a hydroxylgroup, incorporated into an organic group which is linked to thepolymer, and/or incorporated into a cross-link as part of the link or asa substituent on the link.

In various embodiments, attachment of such non-protein organic orinorganic groups to the polymer can be used to modify the hydrophilicityand the degradation rate and mechanism of the polymer. In variousembodiments, protecting group chemistry can be used to modify thehydrophilicity of the material.

In various embodiments, to, for example, facilitate controlling and/orregulating polymer interaction with cells; biomolecules and/or bioactiveagents may be coupled to the hydroxyl groups or integrated into thepolymer backbone. In various embodiments, biomolecules and/or bioactiveagents are encapsulated within the compositions and materials of thepresent inventions. In various embodiments, the biomolecules and/orbioactive agents are attached to the polymer, e.g., covalently,non-covalently, etc., and attachment can result in a slower releaserate.

In various embodiments of compositions and materials of the presentinventions including one or more biomolecules and/or bioactive agents,the cross-link density of one or more types of cross links is adjustedby adjusting the degree fo acrlytaion, the proportion of one or moreco-polymers, or both, to provide an elastomeric composition or materialthat has a desired biomolecule and/or bioactive agent release rate,release profile, or both.

In various embodiments, for example, biomolecules such as growth factorscan be incorporated into a wound dressing/sealent comprising acomposition or material of the present inventions to recruit cells to awound site and/or promote specific metabolic and/or proliferativebehavior in cells that are at the site and/or seeded within the matrix.Exemplary growth factors include, without limitation, TGF-β, acidicfibroblast growth factor, basic fibroblast growth factor, epidermalgrowth factor, IGF-I and II, vascular endothelial-derived growth factor,bone morphogenetic proteins, platelet-derived growth factor,heparin-binding growth factor, hematopoetic growth factor, and peptidegrowth factor. In various embodiments, integrins and cell adhesionsequences (e.g., the RGD sequence) can be attached to the compositionsand materials of the present inventions to facilitate cell adhesion. Invarious embodiments, extracellular matrix components, e.g., collagen,fibronectin, laminin, elastin, etc., can be combined with compositionsand materials of the present inventions to manipulate cell recruitment,migration, and metabolism and the degradation and mechanical propertiesof the material.

In various embodiments, proteoglycans and glycosaminoglycans can becovalently or non-covalently attached to compositions and materials ofthe present inventions.

Tissue Engineering Applications

The elasticity and ability to “tailor” the chemical and physicalproperties of the compositions and materials of the present inventionsrecommends various embodiments for use in regenerating a variety oftissues. In various embodiments, for example, the compositions andmaterials of the present inventions can be used to tissue engineer,epithelial, connective, nerve, muscle, organ, and other tissues, as wellas artery, ligament, skin, tendon, kidney, nerve, liver, pancreas,bladder, and other tissues. In various embodiments, compositions andmaterials of the present inventions can be used as the template formineralization and formation of bone.

Tissues typically experience mechanical forces and deformation in dailyuse, and tissue remodeling is often influenced by mechanical forces. Forexample, heart and other muscle will increase in density and size whenthey are frequently used and will atrophy under disuse. Mechanical forcestimulates the cells that produce extracellular matrix elements toproduce growth factors that promote either the production or degradationof ECM. Use of a substance, like various embodiments of the compositionsand materials of the present inventions, that mimics a normalphysiological response to mechanical forces can facilitate theregeneration of normal tissue, as mechanical stimulation can be appliedearly in the culturing of tissue engineered constructs.

For example, various embodiments of compositions and materials of thepresent inventions can be used to tissue engineer or regenerate aportion of a patient's bladder. In various embodiments, smooth musclecells and urothelial cells are seeded onto compositions and materials ofthe present inventions. The cells can be allowed to proliferate beforethe implant is placed into a patient. To replace or regeneratecartilage, chondrocytes can be seeded onto various embodiments of thecompositions and materials of the present inventions, which canwithstand the cyclic shear and compressive forces cartilage is subjectedto as joints bend.

In various embodiments, compositions and materials of the presentinventions may also be used to produce prosthetic heart valves. Heartvalves are very flexible and are subjected to cyclic deformation as theheart beats. The body repairs tears in heart valve through normalphysiologic mechanisms and thus can regenerate heart valves made ofbiodegradable materials. In various embodiments, the present inventionsprovide a compositions and materials of the present inventions formed inthe shape of a heart valve and seeded with smooth muscle cells andendothelial cells to facilitate remodeling in the body to produce a new,non-synthetic heart valve. In various embodiments, it may be desirableto add fibroblasts. In preferred embodiments, the regeneration occursover a period of 3 months, where the degradation rate of the polymer iscontrolled by modifying the cross-link density, by modifying theproportion of co-polymer, or both.

The shape of the compositions and materials of the present inventionscan be manipulated for specific tissue engineering applications as wellas other applications. Exemplary shapes include particles, tubes,spheres, strands, coiled strands, films, sheets, fibers, meshes, andothers. In various embodiments, microfabrication can be used to formcapillary networks from compositions and materials of the presentinventions. For example, a silicon wafer is processed using standardmicrofabrication techniques to produce a capillary network having adesired pattern. The network is coated with a sacrificial layer, forexample, sucrose. The acrylated pre-polymer mixture (which can comprisea co-polymer) is cast over the sacrificial layer and cured according toa method described herein. Water can be used to dissolve the sacrificiallayer and release the polymerized compositions and materials of thepresent inventions, which will have a relief pattern of the capillarynetworks that had been formed in the silicon wafer. In variousembodiments, the channels in the compositions and materials of thepresent inventions are about 7 μm across and about 5 μm deep. It is tobe understood, that while the size limit for the channels is dictated bythe resolution of the microfabrication technique, biologicalapplications may benefit from channel sizes on the order of 5 to 10's or100's of microns or larger. The capillary networks can be closed bycovering them with a flat sheet of compositions and materials of thepresent inventions and curing it. For example, a layer of uncrosslinkedpolymer can be used as a glue between the patterned layer and the flatlayer. Polymerizing the “glue” can knit the two pieces together. Furthercuring of the assembly can increase the cross-link density of the glueand form covalent bonds between the glue and the flat and patternedcompositions and materials of the present inventions layers. In variousembodiments, an uncrosslinked flat compositions and materials of thepresent inventions film can be cured over a patterned film to cover thechannels.

These shapes can be exploited to engineer a wide variety of tissues. Forexample, the polymer can be fabricated into a tube to facilitate nerveregeneration. The damaged nerve is fed into the end of the tube, whichguides the migration of axons across the wound site. In variousembodiments, compositions and materials of the present inventions can beused to fabricate the tissue structures of liver. For example, formedinto a network of tubes that mimic a blood vessel and capillary networkwhich can be connected to a nutrient supply to carry nutrients to thedeveloping tissue. Cells can be recruited to the network of tubes invivo, and/or it can be seeded with blood vessel cells. Around thisnetwork of tubes, compositions and materials of the present inventionscan be formed into networks imitating the arrangements of extracellularmatrix in liver tissue and seeded with hepatocytes. Similarly, variousembodiments of the compositions and materials of the present inventionscan be fabricated into a fibrous network, seeded with islet cells, andused to tissue engineer pancreas. The compositions and materials of thepresent inventions can also be seeded with a variety of other cells, forexample, tenocytes, fibroblasts, ligament cells, endothelial cells,epithelial cells, muscle cells, nerve cells, kidney cells, bladdercells, intestinal cells, chondrocytes, bone-forming cells, stem cellssuch as human embryonic stem cells or mesenchymal stem cells, andothers.

Medical Applications

Other medical applications may also benefit from the elasticity of thepolymer of the invention. For example, after abdominal surgery, theintestines and other abdominal organs tend to adhere to one another andto the abdominal wall. It is thought that this adhesion results frompost-surgical inflammation, however, anti-inflammatory drugs delivereddirectly to the abdominal region dissipate quickly. In variousembodiments, compositions and materials of the present inventions can beused to deliver anti-inflammatory drugs to the abdominal region. Becausethe compositions and materials of the present inventions can be providedin embodiments that are soft and flexible, yet biodegradable, they canbe implanted between the abdominal wall and internal organs, forexample, by attaching it to the abdominal wall, without cutting internalorgans, which would lead to infection. The anti-inflammatory drug can bereleased from the compositions and materials of the present inventionsover a period of time, e.g., months. While previous researchers haveattempted to use hydrogels, hyaluronic acid-based membranes, and othermaterials to solve these problems, such materials tend to degradequickly in the body; a longer resident period is necessary to preventadhesion.

In various embodiments, compositions and materials of the presentinventions can be used to coat a metallic stent. Because compositionsand materials of the present inventions can be provided in embodimentsthat are flexible, it will expand with the stent without ripping, whilethe stiffness of the metal stent will prevent the compositions andmaterials of the present inventions from elastically assuming itsprevious shape. The compositions and materials of the present inventionscan be include one or more anti-coagulant and/or anti-inflammatoryagents to facilitate preventing, e.g., the formation of clots or scartissue. Angiogenic agents can be included to promote the remodeling ofthe blood vessel surrounding the stent.

In various embodiments, compositions and materials of the presentinventions can also be used to prepare “long term” medical devices.Unlike typical permanent medical devices, compositions and materials ofthe present inventions can be made to degrade over time, for example,they can be fabricated into a biodegradable cardiac stent. Preferably,compositions and materials of the present inventions are combined with aharder polymer that plastically forms for the production of stents. Invarious embodiments, the compositions and materials of the presentinventions acts as a plasticizer that enables the stent to expand intothe desired shape after implantation. The stent increases the diameterof the blood vessel to allow easier circulation, but, because the stentis biodegradable, surrounding blood vessels increase in diameter withoutthrombosis or covering the stent with scar tissue, which could reclosethe blood vessel. The time the stent should remain in place and retainits shape before degradation will vary from patient to patient anddepend partially on the amount of blockage and the age of the patient(e.g., older patients require more time to heal). Using the teachingspresented herein, one of ordinary skill in the art can adjust one ormore of, e.g., the DA, the cross-link density, and the co-polymerproportion in thoise embodiments having a co-polymer, to adjust thedegradation rate. As for the coated stent, a degradable stent of thepresent invention can also release biomolecules, bioactive agents, orsome combination of these in situ.

In various embodiments, the compositions of the present inventions canbe used as surgical glue. A biocompatible, biodegradable surgical gluecould be used to stop bleeding during surgery but does not need to beremoved before the surgeon sutures the wound closed and will degradeover time. Current surgical glues often use fibrin derived from bovinetissue, and a synthetic surgical glue reduces the risk ofCreuzfeld-Jakob syndrome (“mad cow disease”). To produce a glue, it ispreferred to increasing the number of hydroxyl groups (e.g., by reducingthe cross-link density), and rendering the product exceedingly sticky.In various embodiments, a surgical glue of the present invention has across-link density less than 1%, preferably less than 0.5%, and morepreferably less than 0.05%.

In various embodiments, compositions and materials of the presentinventions can be used to support in vivo sensors and catheters. Thepolymer can be constructed into a chamber for an optical fiber-basedsensor or a coating for a catheter that is inserted into the area ofinterest. In a sensor, the chamber can contain a specificchromophore-bonded receptor for the molecule of interest. When ananalyte attaches to the receptor, the chromophore will either emit orabsorb light at an specific wavelength. The absorption or emission maybe detected by an apparatus connected to the optical fiber. The sensormay be used for, for example, short term, continuous monitoring, for tento fifteen days. Likewise, a catheter may be used to periodicallydeliver drugs or other small molecules or bioactive agents to a specificsite or intravenously. Use of various embodiments of the compositionsand materials of the present inventions can reduce the formation of scartissue which would ordinarily form around a shunt or other implant thatis used for more than two weeks. It is preferred, in variousembodiments, that the degradation rate of the compositions and materialsof the present inventions are chosen so that there is no significantdegradation of the material while it is in place in the patient.

Drug Release Applications

In various embodiments, compositions and materials of the presentinventions can be used for drug release applications, for example, inapplications where the matrix retaining the drug needs to be flexible.Because compositions and materials of the present inventions can provideembodiments that are elastic, they can move with the patient as he/shewalks, runs, sits, etc. Because compositions and materials of thepresent inventions can provide embodiments that maintain theirmechanical integrity as they degrades, the device is less likely to failcatastrophically toward the end of its lifetime, reducing the risk of abolus release of the desired agent. Biomolecules and bioactive agentscan all be combined with various embodiments of the compositions andmaterials of the present inventions using covalent or non-covalentinteractions. Exemplary non-covalent interactions include hydrogenbonds, electrostatic interactions, hydrophobic interactions, and van derWaals interactions.

In various embodiments, compositions and materials of the presentinventions may also be used for other wounds that are hard to close orthat fail to heal properly through normal physiologic mechanisms. Forexample, diabetics often get skin injuries (“diabetic ulcers”),especially in the lower extremities, that take a long time to heal orfail to heal properly due to poor circulation. The use of variousembodiments of the compositions and materials of the present inventionsto deliver antibiotics or anti-inflammatory agents to these wounds canaid healing and provide a cover for the wound.

Non-Medical Applications

In various embodiments, compositions and materials of the presentinventions can be used for non-medical applications. For example,diapers are formed from a tough elastomer and liquid-permeable topsheetthat encase an absorbent material. Currently, polypropylene is used forthe elastomeric “casing”. Polypropylene is not degradable and requiresten or more years to break down in a landfill. In contrast, compositionsand materials of the present inventions can provide embodiments that arestable in a dry environment but will degrade in a landfill within two tofour weeks after becoming wet. Similar products that can exploit thebiodegradability of compositions and materials of the present inventionsinclude incontinence protectors, sanitary napkins, panty liners, andwound dressings. Likewise, plastic bags, e.g., trash bags, can be madepartially or entirety of various embodiments of the polymers of thepresent inventions. Where compositions and materials of the presentinventions are used alone, it may be desirable to increase thecross-link density, and/or increase the proportion of co-polymer, and/ormodify the hydroxyl groups to increase the degradation time and preventsignificant degradation before the bag reaches the landfill.

In various embodiments, compositions and materials of the presentinventions can be exploited to protect not only natural resources butthe animals that depend on those natural resources. For example, it isvery popular to release helium filled balloons at various public events.The balloons eventually pop and drift back down to earth, where animalsmay choke while attempting to eat them. In contrast, balloons made outof various embodiments of the compositions and materials of the presentinventions would degrade upon exposure to the elements. Such balloonscould eventually be digested by animals that eat them and would notpresent a continuing choking risk to animals once they degraded. Invarious embodiments, compositions and materials of the presentinventions may be used to fabricate fishing lures or flies. When afisherman loses a lure, the lure will simply sink to the bottom of thestream or lake and eventually degrade.

In another non-medical application, various embodiments of thecompositions and materials of the present inventions can be used as abase for chewing gum. For example, the material may be combined with acolorant, flavor enhancer, or other additive to produce a gum. Theappropriate microstructure to produce a pleasant mouthfeel duringchewing can be determined by polymerizing the polymer to differentmolecular weights and cross-link densities and chewing the resultingmaterial for a few minutes.

The gum can also be adapted to deliver nutrients (e.g., vitamins) ordrugs to the chewer. Nutrients may include FDA-recommended nutrientssuch as vitamins and minerals, amino acids, or various nutritionalsupplements available at health food stores. Such additives may simplybe mixed with the acrylated pre-polymer (with or without a co-polymer)to produce a gum. In various embodiments, the nutrients can becovalently attached to the polymer, preferably through hydrolyzablebonds or bonds that are lysed by the enzymes found in the mouth. As thegum is chewed, the nutrient or drug is released and swallowed.

EXAMPLES

Aspects of the present inventions may be further understood in light ofthe following examples, which are not exhaustive and which should not beconstrued as limiting the scope of the present inventions in any way.

The following examples provide examples of the preparation of PGSAnetworks and compare the properties of: (a) thermally curedpoly(glycerol sebacate) (PGS); (b) photocured poly(glycerolsebacate)-acrylate (PGSA); and (c) and photocured poly(glycerolsebacate)-acrylate-co-poly(ethylene glycol) (PGSA-PEG) networks. In theExamples, these polymers were examined for their degradationcharacteristics (in vitro and in vivo), mechanical properties andbiocompatibility in vivo.

Example 1: PGS, PGSA and PGSA-PEG Copolymers Synthesis of the PrePolymer and Acrylated Pre Polymer

All chemical were purchased from Sigma-Aldrich (Milwaukee, Wis., USA),unless stated otherwise. pre-polymer was synthesized by polycondensationof equimolar glycerol and sebacic acid (Fluka, Buchs, Switzerland) at120° C. under argon for 24 h before reducing the pressure from 1 torr to40 mtorr over 5 h, resulting in a viscous liquid. The acrylation of thepre-polymer was prepared from the pre-polymer without furtherpurification. The polycondensation was continued for another 24 h,yielding a viscous pre-polymer. This material was used without furtherpurification.

A flame-dried round-bottom flask was charged with PGS pre-polymer (20 g,with 78 mmol hydroxyl groups), 200 mL anhydrous dichloromethane, to makea 10% solution (w/v). After adding 20 mg 0.18 mmol) of the catalyst4-(dimethylamino)-pyridine (DMAP), the reaction flask was cooled to 0°C. under a positive pressure of nitrogen and stirred. Once cooled, 0.1to 1.1 (mol/mol) acryloyl chloride (0.25-0.80 mol per mol hydroxylgroups on PGS pre-polymer) to glycerol-sebacate was slowly added tostart the reaction, and an equimolar amount of triethylamine to acryloylchloride was added in parallel. The mixture was allowed to heat up toroom temperature and stirred for an additional 24 h under nitrogen. Theproduct was dissolved in ethyl acetate to precipitate the chloridesalts, filtered and dried at 45° C. and 5 Pa providing a viscous liquid.

Characterization of the Pre Polymer and Acrylated Pre Polymer

Pre-polymer and acrylated pre-polymer samples were dissolved in CCl₃Dand ¹H Nuclear Magnetic Resonance (¹H-NMR) spectra were recorded on aVarian Unity-300 NMR spectrometer. Chemical shift in ppm for NMR spectrawere referenced relative to CCl₃D at 7.27 ppm. Composition wasdetermined by calculating the signal intensities of —COCH₂ —CH₂ —CH₂ —at 1.2, 1.5, 2.2 ppm for the sebacic acid, —CH₂ —CH— at 3.7, 4.2 and 5.2ppm for glycerol and —CH═CH₂ at 5.9 ppm, 6.1 ppm and 6.5 ppm for theprotons on the methylene groups. The signal intensity of the methylenegroups of the sebacic acid (1.2 ppm) and the acrylate groups (averagesignal intensity of 5.9, 6.1 and 6.5 ppm) were used to calculate thedegree of acrylation (DA).

The PGS pre-polymer had a weight average molecular weight (Mw) of 23 kDaand a molar composition of approximately 1:1 glycerol:sebacic acid, asconfirmed by GPC and ¹H-NMR analyses. Example spectra are shown in FIGS.8A and 8B. FIG. 8A showing a spectrum of PGS pre-polymer and FIG. 8B ofPGSA. Referring to FIGS. 8A and 8B, the sebacic acid and glycerol in thepolymer matrix were identified at 1.2, 1.5, 2.2 ppm and 3.7, 4.2 and 5.2ppm by hydrogens located on the carbons labeled ‘a’-′e′ in the figures.Vinyl groups located on the PGSA were identified at 5.9 ppm, 6.1 ppm and6.4 ppm labeled ‘f’-′i′ in the figures, where the region about g, f andI has been expanded in the inset 8X02.

FIGS. 9A and 9B compare ATR-FTIR spectra of: PGS pre-polymer PGSpre-polymer (902); PGSA with a DA of 0.20 (904); PGSA (DA=0.54) (906);thermally cured PGS (908); photocured PGSA (DA=0.20) (910); andphotocured PGSA (DA=0.54) (912). The formation of a polymer networkafter photocuring of PGSA is confirmed by the increase of the band at2930 cm⁻¹ corresponding to the vibration of methylene groups and theelimination of the band at 1375 cm⁻¹ corresponding to the vibration ofthe vinyl bonds.

The incorporation of acrylate groups was confirmed by the appearance ofthe peaks at □□5.9, 6.1 and 6.4 ppm (compare FIGS. 8A and 8B) and byATR-FTIR by the appearance of the band at 1375 cm⁻¹ corresponding to thevibration of the vinyl bond (compare FIGS. 9A and 9B). About 66% of theacryloyl chloride added in the was incorporated in the prepolymer ascalculated from signal intensities of ¹H-NMR, consequently the degree ofacrylation ranged from 0.17 to 0.54 as shown in FIG. 10. In addition,the NMR data show that acryloyl chloride apparently reactspreferentially with the hydroxyl groups from glycerol compared with thecarboxylate groups from sebacic acid. This was indicated by the increaseof signal integral at □□5.2 ppm corresponding to the resonance ofprotons from the tri-substituted glycerol and the decrease of signalintegral at about □□3.7 ppm corresponding to the resonance of protonsfrom mono-substituted glycerol (compare FIGS. 8A and 8B) with theincreasing of DA. ¹H-¹H COSY NMR; and quantitative ¹³C-NMR analysisshowed minimal (<5%) substitution of terminal carboxylate groups (datanot shown). The M_(w) of the PGSA remained substantially unchanged afteracrylation.

The PGS pre-polymer and PGSA were sized using gel permeationchromatography (GPC), using THF on Styragel columns (series of HR-4,HR-3, HR-2, and HR-1, Waters Corp., Milford, Mass., USA).

Preparation of Photocured PGSA Networks

PGSA networks were formed by mixing PGSA with 0.1% (w/w) photo initiator(2,2-dimethoxy-2-phenyl-acetophenone) and the polymerization reactioninitiated by ultraviolet light at about 4 mW/cm², between two glassslides with a 1.2 mm spacer, for 10 minutes using a longwave ultravioletlamp (model 100AP, Blak-Ray). Attenuated total reflectance-Fouriertransform infrared spectroscopy (ATR-FTIR) analysis was performed on aNicolet Magna-IR 500 spectrophotometer to confirm the crosslinkreaction. The samples analyzed: (a) thermally cured PGS slabs; (b)photocured PGSA slabs, (c) PGS pre-polymer, and (d) PGSA; were firstdissolved in chloroform and then placed on top of the crystal.

Copolymerization of PEG Diacrylate and PGSA

Networks of PGSA-PEG diacrylate were prepared by mixing 10, 50, 90%(wt/wt) PGSA (DA=0.34) with PEG diacrylate (Mw=700 Da) including 0.1%(w/w) photoinitiator, followed by photopolymerization under ultravioletlight between two glass-slides with a 1.2 mm spacer, for 10 minutes. Thephotocured networks were soaked in 100% ethanol for 24 h and soaked inphosphate buffer saline (PBS) for 24 h prior to mechanical testing.Poly(ethylene glycol) hydrogels were prepared from a PEG diacrylatesolution (20%, w/w, in water) containing 0.1% (w/w) photoinitiator,followed by photopolymerization using the conditions described above.The swelling ratio in PBS was determined as described below.

Thermal and Mechanical Properties

The thermal properties of discs from thermally cured PGS, photocuredPGSA (DA=0.31, 0.54) and PGSA (DA=0.34+5% PEG diacrylate) werecharacterized using differential scanning calorimetry (DSC), DSC Q 1000,2 cycles, within the temperature range of −90° C. and 250° C. using aheating/cooling rate of 10° C. The glass transition temperature (Tg) wasdetermined as the middle of the recorded step change in heat capacityfrom the second heating run.

Tensile strength tests were conducted on dog-bone-shaped polymer strips(115×25×1.2 mm) cut from photocured PGSA sheets and were tested using anInstron 5542 substantially according to ASTM standard D412-98a. Theelongation rate was 50 mm/min and all samples were elongated to failure.Values were converted to stress-strain and the tensile Young's moduluswas calculated from the initial slope (0-10%). All the mechanicaltesting was performed under wet conditions (soaked in PBS for 24 h.)after sol content removal. The sol content, or unreacted macromers, wereremoved by soaking the PGSA sheets in ethanol for 24 h. To assess thesol content, swelling properties and the dry mass of photocured PGSA,discs (10×2 mm) (n=3) were weighed (W₀) and immersed in 5 mL of ethanol.After soaking the samples in ethanol for 24 h the polymer was dried at90° C. for 7 days and re-weighed (W₁) to determine the percentage ofunreacted macromers, the sol content (W_(sol)), by the following formulaW_(sol)=[((W₀—W₁)/W₁)×100]. The photocured PGSA discs (without solcontent) were soaked in phosphate buffer saline (PBS) for 24 h, surfacePBS was removed with a tissue paper and samples were re-weighed (Ws).The swelling ratio (SR) was determined by: SR=[(Ws−W₀)/(W₀)×100] andexpressed as a percentage of W₀. The swelling ratio of photocured PGSAin ethanol was assessed in the same manner.

To determine the density of the photocured PGSA, a 50 mL pycnometerbottle (Humboldt, MFG. Co.) was used to measure the volume ofpre-weighed polymer sample (n=10). The density and Young's modulus ofthe samples were used to calculate the crosslinking density and relativemolecular mass between crosslinks (Mc) substantially as described in,Wang Y, Ameer G A, Sheppard B J, Langer R., Nat. Biotechnol 20(6): pp602-6 (2002), the entire contents of which are incorporated herein byreference.

In Vitro Degradation

To assess full degradation via hydrolysis and relative degradation ratesamong samples, discs of dry thermally cured PGS, photocured PGSA(DA=0.31, 0.54), and PGSA (DA=0.34+5% PEG diacrylate) polymers (diameter10′1.6 mm) were weighed (W0) and immersed in 20 mL of 0.1 mM NaOH at 37°C. Prior to the degradation study the sol content was removed, asdescribed above. At 5 different time points (0, 1.5, 3, 4.5, and 6hours) samples (n=3) were removed from 0.1 mM NaOH and washed withdeionized water. Samples were dried at 90° C. for 7 days and weighed(Wt) again. The remaining dry mass [(Wt/W0)′100] was calculated. Forsurface analysis of the degraded samples by scanning electronmicroscopy, dry samples were sputter-coated with platinum/palladium(about a 250 Angstrom thick layer), mounted on aluminum stubs withcarbon tape and examined on a JEOL JSM-5910 scanning electronmicroscope.

In Vitro Cell Attachment and Proliferation

Photocured PGSA (DA=0.34) spin coated discs (diameter 18 □□1 mm) (n=3),prepared with 20% PGSA in dimethylsulfoxide (DMSO) at 3,400 rpm for 5min followed by a 10 min UV polymerization, were used in this study. Toensure successful PGSA spin coating and subsequent photocuring, discswith and without UV curing were submerged in Chloroform for 24 h, whereunreacted macromers are expected to dissolve. The resultant surfaceswere examined using light microscopy. Cell culture medium, Dulbecco'sModified Eagle Medium (DMEM) with 10% fetal bovine serum and 1%Penicillin/Streptomycin, was used as growth medium. The photocured spincoated PGSA discs were incubated with growth medium in a 12 well platefor 4 h in order to remove photo initiator, residual DMSO, and anyunreacted monomers prior to human foreskin fibroblast cell (ATCCCRL-2522) seeding. Each disc was seeded with 5,000 cells/cm 2 using 2 mLof growth medium. The cells were incubated in a 5% Co₂ humidifiedincubator at 37° C. After incubation for 4 h the cultures were washedwith PBS twice to remove unattached cells and incubated with cellculture medium. Cells were fixed with 4% formaldehyde solution for 10min and washed with PBS for 4 hours, 2, 5 and 12 days. The cells werethen counted at nine random equally sized spots (0.005 cm²) under lightmicroscopy and the cell density was calculated.

Characterization and Comparison of Properties of Cured PGS and PGSA

The UV polymerization of PGSA in the presence of the photoinitiator2-dimethoxy-2-phenyl-acetophenone yielded elastomeric networks. ATR-FTIRanalysis of the photocured PGSA elastomers (FIG. 9A) shows an increaseof the band at 2930 cm⁻¹ corresponding to the vibration of methylenegroups and a decrease of the band at 1375 cm⁻¹ corresponding to thevibration of the vinyl bonds. This indicates that most of the vinylgroups participated in the crosslinking reaction. The broad peak at 3475cm⁻¹ was assigned to hydrogen bonded hydroxyl groups. It is believedthat these hydrogen bonded hydroxyl groups arise from free hydroxylgroups which are not modified by acryloyl chloride. The Tg of thermallycured PGS, photocured PGSA (DA=0.31, 0.54) and PGSA (DA=0.34+5% PEGDiacrylate) were, respectively, −28.12, −32.2, −31.1 and −31.4° C. Theseresults indicate that thermally cured PGS and photocured PGSA areamorphous at 37° C. Further data on the physical properties of thephotocured PGSA is given in Table 1.

TABLE 1 Relative molecular PGSA degree Young's Ultimate Crosslinkingmass between of acrylation Density modulus Elongation strength densitycrosslinks (DA) (g/cm3) (Mpa) (%) (Mpa) (mol/m3) (Mc) (g/mol) 0.17 1.21{0.02} 0.048 {0.005} 170 {17.2} 0.054 {0.005} 6.4 {0.7} 18906 {232} 0.201.19 {0.02} 0.148 {0.004} 101 {26.5} 0.109 {0.011} 19.8 {0.6} 6013 {253}0.31 1.16 {0.02} 0.383 {0.028} 54.7 {14.1} 0.163 {0.034} 51.5 {3.9} 2262{185} 0.34 1.15 {0.01} 0.568 {0.222} 60.1 {5.73} 0.270 {0.032} 76.4{3.0} 1514 {73.3} 0.41 1.15 {0.02} 0.895 {0.052} 51.1 {7.41} 0.364{0.034} 120.4 {7.0} 953.9 {69.1} 0.54 1.15 {0.01} 1.375 {0.084} 47.4{11.3} 0.498 {0.079} 185.0 {11.3} 620.1 {42.4}

The Young's modulus and ultimate tensile strength of the photocured PGSAwas linearly proportional to the DA (data is presented in FIGS. 11A, 11Band Table 1); no permanent deformations were observed after mechanicaltesting. The mechanical properties of the photocured PGSA spanned fromsoft to relatively stiff as determined by the tensile Young's modulus ofthe polymer, which varied from about 0.05 MPa (DA=0.17) to about 1.38MPa (DA=0.54). The ultimate tensile strength ranged from about 0.06 MPato about 0.47 MPa (FIG. 3B) whereas the strain to failure of photocuredPGSA ranged from about 189% to about 42% with increasing DA. The degreeof swelling of the elastomeric networks in ethanol and water ranged,respectively, from about 50 to about 70%, and from about 8 to about 12%.The degree of did not change appreciably as a function of DA. The highdegree of swelling in ethanol can facilitate removal of unreactedmonomers or potential incorporation of specific factors. The low degreeof swelling in water can facilitate, e.g., maintaining the mechanicalproperties upon implantation.

The sol content of the polymer decreased from about 40% to less thanabout 10% by increasing the DA from about 0.20 to about 0.54 (data ispresented in FIG. 11C). It is believed that this is a consequence of theincreasing number of new crosslinks between the polymer chains andtherefore directly related to the crosslink density. The high solcontent that is achieved with a lower DA (softer materials) might beunfavorable, for example, for in situ polymerization where unreactedmacromers might diffuse into the surrounding tissue. It was observedthat the mechanical properties (measured without sol content) aresubstantially linearly proportional to the DA, which is correlated tothe formation of new crosslinks within the polymer network.

The density of the photocured elastomeric discs was seen to decreaseslightly with increasing DA (data is presented in Table 1), which issimilar to other thermally cured elastomers in which the density isinversely proportional to the curing time. The density and Young'smodulus of the samples was used to calculate the crosslinking densityand relative molecular mass between crosslinks (Mc) (data is presentedin Table 1). Increasing the DA in photocured PGSA from about 0.17 toabout 0.54, increased the crosslinking density from about 6.4 to about185 mol/m³ and decreased the relative molecular mass between crosslinksfrom about 18 kDa to about 0.6 kDa.

Copolymerization of PEG Diacrylate and PGSA

In various embodiments, the present inventions provide a photocurablePGSA composition comprising acrylated hydrogel precursors. In variousembodiments, the inclusion of an acylated hydrogel can be used toimpart, for example, one or more of mechanical, biodegradable, andswelling properties that, for example, are not normally associated withmore common hydrogel materials. FIG. 12 presents some data on thevariation of properties of a photocurable PGSA composition comprisingvarious portions of an acrylated hydrogel. Most hydrogel materials arevery fragile and have poor mechanical properties. For example, ahydrogel formed from 20% (w/w) poly(ethylene glycol) diacrylate (700 Da)in water exhibits an elongation of 14%, Young's modulus of 0.54 MPa andultimate strength of 0.063 MPa. Through combining PEG diacrylate withPGSA (DA=0.34), the Young's modulus, ultimate strength, elongation andswelling ratio can be varied (see data presented in FIG. 12). Forexample, through increasing the concentration of PGSA, the elongationincreased from about 4 to about 60%, Young's modulus decreased fromabout 20 Mpa to about 0.6 MPa and ultimate strength decreased from 0.890Mpa to about 0.270 MPa. The networks formed by the copolymerization ofPEG diacrylate with PGSA (DA=0.34) (50:50) showed a ten fold higherYoung's modulus and ultimate strength than the typical PEG diacrylatehydrogel while maintaining elongation. Furthermore, the swellingbehavior of these networks was tuned from about 40% to about 10% throughchanging the concentration of PGSA from about 10% to about 90%.

In Vitro Degradation Results

To examine the relative differences in terms of degradation between thePGS and PGSA polymer networks, a degradation study was performed usinghigh pH to accelerate the hydrolysis. Therefore, photocured PGSA(DA=0.31 and 0.54), PGSA (DA=0.34 copolymerized with 5% PEG diacrylate)and PGS were degraded in a sodium hydroxide (0.1 mM) solutionsubstantially as describe in, Yang J, Webb A R, Pickerill S J, HagemanG, Ameer G A. Biomaterials; 27(9), pp. 1889-98 (2006), the entirecontents of which are incorporated herein by reference. Photocured PGSA(DA=0.31 and 0.54) showed a similar degradation profile as PGS. However,the mass loss of PGSA (DA=0.31) was significantly (P<0.01) highercompared to PGS and PGSA (DA=0.54). The mass loss of PGSA (DA=0.34copolymerized with 5% PEG diacrylate) was significantly (P<0.01) lowercompared to PGS and PGSA (DA=0.54) after 3 hours of degradation insodium hydroxide. Copolymerization of 5% PEG diacrylate with PGSA(DA=0.34) resulted in polymers with similar mechanical properties (seeabove and FIG. 12), yet slower degradation rates compared to photocuredPGSA (DA=0.54) and PGS, as illustrated in FIG. 13. These resultsindicate that the in vitro hydrolytic degradation rate of photocuredPGSA can be decreased, independent of the starting mechanical strength.SEM analysis of all degraded materials after 3 h in sodium hydroxideshow no observable deterioration of gross morphology, or formation ofcracks or tears on the surface of the material (SEM data is present inFIG. 14A). Thermal analysis of all degraded materials after 3 h insodium hydroxide did not show appreciable change in Tg.

In Vitro Cell Attachment

In vitro cell culture shows that various embodiments of the photocuredPGSA elastomers of the present inventions support cell adhesion andproliferation. It was observed 59±12% of the human foreskin fibroblastscells seeded on photocured PGSA attached after 4 h and were viable. Theattached cells proliferated, forming a confluent cell monolayer (seeFIGS. 14A, 14B and 14C), indicating that in various embodiments aphotocured PGSA of the present inventions can function as a celladhering biomaterial.

Example 2: In Vivo Data and Biocompatability

This example presents data on the modulation of the mechanicalproperties and the degradation rate of various embodiments of a PGSAcomposition of the present invnetions. Data is presented on the effectsof varying the density of acrylate groups in the polymer backbone anddata is presented for copopsitions of PGSA copolymerized with variousproportions of low molecular weight poly (ethylene glycol) diacrylate.Data is presented on the influence of these modifications on thebiomaterial's degradation mechanism and rate (in vitro and in vivo) andthe mechanical properties and biocompatibility in vivo.

Materials and Methods Synthesis of the Pre Polymer and Acrylated PrePolymer

All chemical were purchased from Sigma-Aldrich (Milwaukee, Wis., USA),unless stated otherwise. Both PGS and PGSA were synthesizedsubstantially as described in, Wang Y, Ameer G A, Sheppard B J, LangerR., Nat. Biotechnol 20(6): pp 602-6 (2002), the entire contents of whichare herein incorporated by reference. The PGS pre-polymer wassynthesized by polycondensation of equimolar glycerol and sebacic acid(Fluka, Buchs, Switzerland) at 120° C. under argon for 24 h beforereducing the pressure from 1 torr to 40 mtorr over 5 h. Thepolycondensation was continued for another 24 h, yielding a viscouspre-polymer. For the PGSA synthesis, the PGS pre-polymer was usedwithout further purification. PGSA was synthesized with a low number ofacrylate groups (PGSA-LA) and a high number of acrylate groups (PGSA-HA)on the backbone substantially as described in Example 1. For thispurpose, 20 g of the PGS pre-polymer (with 78 mmol hydroxyl groups), 200mL anhydrous dichloromethane and 4(dimethylamino)-pyridine (DMAP) (20mg, 1.8(10⁻⁴) mol) were charged into a reaction flask. The reactionflask was cooled to 0° C. under a positive pressure of nitrogen. For thePGSA-LA, acryloyl chloride (37 mmol) was slowly added parallel to anequimolar amount of triethylamine. For the PGSA-HA acryloyl chloride (48mmol) was slowly added parallel to an equimolar amount of triethylamine.The reaction was allowed to reach room temperature and was stirred foran additional 24 h. The resulting mixture was dissolved in ethylacetate, filtered and dried at 45° C. and 5 Pa.

Photocured PGSA-LA and PGSA-HA sheets were formed by mixing PGSA with0.1% (wt/wt) photoinitiator (2,2-dimethoxy-2-phenyl-acetophenone) andthe polymerization reaction initiated by ultraviolet light, at a powerdensity of about 4 mW/cm², from a ultraviolet lamp (model 100AP,Blak-Ray), between two glass slides with a 1.6 mm spacer, for 10minutes. PGSA-LA mixed with 0.1% photo initiator (wt/wt) and 5% (wt/wt)PEG-diacrylate (Mw=700 Da) was photocured as described for PGSA-LA/HA.1.6 mm PGS pre-polymer sheets were thermally cured at 140° C. and 40mtorr for 16 h. The polymer sheets were washed in 100% ethanol for 24 h.to remove any unreacted macromers or photo initiator and dried in theoven at 60° C. for 24 h. 48 h prior to in vivo implantation, the polymersheets were UV radiated in a laminar flow hood for 40 min. to sterilizethe sheets, and then washed in 100, 70, 50, 30% (ethanol/sterilephosphate buffer saline (PBS)) for 10 min. and placed in sterile PBS.

Characterization of the Pre Polymer and Acrylated Pre Polymer

Characterization of the pre-polymers and polymers was conductedsubstantially as described in Example 1.

Implantation

Young adult female Lewis rats (Charles River Laboratories, Wilmington,Mass.) weighing 200-250 g were housed in groups of 2 and had access towater and food ad libitum. Animals were cared for according to theapproved protocols of the Committee on Animal Care of the MassachusettsInstitute of Technology in conformity with the NIH guidelines for thecare and use of laboratory animals (NIH publication #85-23, revised1985). The animals were anaesthetized using continuous 2% isoflurane/O₂inhalation. Two rats per group per time point received implants. Thiswas done by two small midline incisions on the dorsum of the rat and theimplants were introduced in lateral subcutaneous pockets created byblunt dissection. The skin was closed using staples or a single 2-0Ethilon suture. The cranial implants were used for histology and wereresected en bloc with surrounding tissue. The caudal implants wereharvested for the assessment of degradation and mechanical testing. Eachside of the rat carried PGS, PGSA-LA, PGSA-HA or PGSA-PEG implants.Every 7 days the animals were briefly anaesthetized and shaved forinspection and palpation of the implants to assess any wound healingproblems and gross implant dimensions.

In Vitro and In Vivo Degradation

To assess degradation via hydrolysis and enzymes in vitro, cylindricalslabs of dried PGS, PGSA-LA, PGSA-HA and PGSA-PEG (diameter 10×1.6 mm)(n=3) were weighed (W₀) and immersed in 5 mL of PBS, pH 7.4 and in 2 mlPBS with 40 units (94.7 mg) of cholesterol-esterase at 37° C. For thedegradation in PBS, time points were taken at 0 and 10 weeks and for theenzymatic degradation at (4.5, 9, 14, 24 and 48 h.). All samples werewashed with deionized water and surface water was removed with tissuepaper. Samples were then dried at 90° C. for 3 days and weighed (Wt)again. The mass loss [((Wt−W₀)/W₀)×100] was calculated. For the in vivodegradation study, cylindrical slabs of dried photocured PGS, PGSA-LA,PGSA-HA and PGSA-PEG (diameter 10×1.6 mm) (n=4) were implanted. Toassess in vivo degradation PGS, PGSA-LA, PGSA-HA and PGSA-PEG implantswere isolated from the surrounding tissue and collected in PBS. Aftersurgical removal, the explants were weighed (Wt) and sized (St) betweentwo microscope cover slides. Compression tests were performed on theexplants (wet) with a 50N load at a compression rate of 5 mm/min usingan Instron 5542, substantially according to ASTM standard D575-91.Samples were compressed 40%, compression modulus was calculated from theinitial slope (0-10%) of the stress-strain curve. The explants were thenweighed (Ww), dried at 90° C. for 3 days and weighed (Wt) again. Thewater content [((Ww−Wt)/Wt)×100], mass loss [((Wt−W₀)/W₀)×100] and sizeover time [((St−S₀)/S₀)×100] were calculated, where S₀ represents thesize of the implant prior to implantation.

All the explants were cut in half by a razorblade. One half of each ofthe explants were prepared for scanning electron microscope (SEM),sputter-coated with platinum/palladium (about 250 Angstrom layer),mounted on aluminum stubs with carbon tape and examined on a JEOLJSM-5910. The other half was used to assess the sol content of thematerial. For this purpose, the dry explants were weighed (Wd), placedin 100% ethanol for 3 days on a orbital shaker, dried at 90° C. for 3days and weighed (Ws) again to determine the sol content of the explantsby [((Wd−Ws)/Ws)×100].

In Vivo Biocompatibility

Specimens for histology were fixed using a 10% formaldehyde solution andprepared for immunohistochemical staining analysis. The sections werestained using heamatoxylin and eosin (H&E). The H&E stained sectionswere analyzed by a medical doctor experienced in pathology who wasblinded as to the polymer content of the implants. The H&E stains wereused to analyze for the presence of fibroblasts in the capsulesurrounding the material, macrophages in contact with the material, andfor the presence of multinucleated giant cells, ingrowth of cells intothe material and phagocytosis of the material.

Statistical Analysis

Statistical analysis was performed using a homoscedastic two-tailedStudent's t-test with a minimum confidence level of 0.05 for statisticalsignificance. All values are reported as the mean and standarddeviation.

Results

In the following discussion of the results of Example 2, theabbreviation PGSA will refer to photocured poly(glycerolsebacate)-acrylate elastomers and the consecutive abbreviation LA or HAwill refer to degree of acrylation (low or high) on the backbone of thePGS pre-polymer. PGSA-PEG will refer to the photocrosslinked copolymerfrom PGSA-LA (low degree of acrylation) and 5% (wt/wt) poly(ethelyneglycol) PEG diacrylate. PGS will refer to the thermally cured elastomer.

Polymer Characterization

The PGS pre-polymer had a molar composition of approximately 1:1glycerol:sebacic acid as evidenced by ¹H-NMR analyses. The incorporationof acrylate groups was confirmed by ¹H-NMR by the appearance of thepeaks at d 5.9, 6.1 and 6.4 ppm. The degree of acrylation (i.e. ratio ofacrylate groups to glycerol moieties) on the backbone of the pre-polymerwas calculated from the proportion of signal intensities on ¹H-NMR, andwas 0.31±0.02 for PGSA-LA and 0.41±0.03 for PGSA-HA.

The UV polymerization of PGSA in the presence of the photoinitiator2-dimethoxy-2-phenyl-acetophenone yielded elastomeric networks, as didthermally cured PGS. The viscous PGSA pre-polymers formed a clearelastomeric slab within 10 minutes, whereas PGS required 16 h of curing.Increasing the density of the acrylate groups in the pre-polymerincreases, it is believed without being held to theory, the length anddensity of the methylene chains in the network that is formed, which itis believed, without being held to theory, could slow the degradation ofthe biomaterial. The mechanical and thermal properties of the elastomersare summarized in Table 2.

TABLE 2 Degree Young's Crossliking of Tg modulus Elongation densityacrylation (° C.) (Mpa) (%) (mol/m3) PGS — −28 0.76 80 102 PGSA-LA 0.31−32 0.38 55 51.5 PGSA-HA 0.41 −31 0.89 51 120 PGSA-PEG 0.31 −32 0.8 45108

In Vitro Degradation Results

Photocured PGSA and PGSA-PEG samples showed a 5-10% mass loss in PBSover a period of ten weeks. The hydrolytic degradation of PGSA wasobserved to decrease when the degree of acrylation was increased or whenPEG was incorporated. The potential contribution of enzymatic activityto the degradation of these elastomers was assessed by incubation in 40units of pancreatic cholesterol esterase in 2 ml PBS. Pancreaticcholesterol esterase has been reported to be substantially identical tothe esterases associated with macrophages (inflammatory cells) known todegrade polyesters. PGS and PGSA-LA showed a mass loss over time, whilePGSA-HA and PGSA-PEG did not. PGS degraded by 60% over 48 h, whilePGSA-LA, which has a lower crosslinking density, only degraded by 40%(data is presented in FIG. 15). The results suggest that the longmethylene cross-links formed from acrylate groups are less susceptibleto cholesterol esterase than the cross-links formed in PGS.

In Vivo Degradation Results

To assess the degradation characteristics of PGS, PGSA and PGSA-PEGcopolymer in vivo, discs of cross-linked material were implantedsubcutaneously in rats, and harvested at predetermined intervals. Ondissection, the caudal implants were easily separated from surroundingtissue. The geometry and surface properties of the explants wereexamined and changes in mass, water content, sol content and mechanicalstrength over time were observed (data is presented in FIGS. 16A-D and17).

Incorporation of acrylate groups or PEG into the backbone was observedto decrease the degradation of the material (see FIG. 16A): 80% of PGSmass degraded within 5 weeks, while the same mass loss occurred forPGSA-LA over 9 weeks. PGSA-HA degraded even slower with an initial 5%mass loss in the first 5 weeks, followed by an accelerated mass loss to60% at 11 weeks. Degradation was further delayed with the incorporationof PEG in the polymer chain, with a mass loss of approximately 20% after12 weeks in vivo. After 3 weeks in vivo: PGSA-PEG and PGSA-HA mass losswas not significantly different and significantly lower than PGS andPGSA-LA, while PGS mass loss was significantly higher than that ofPGSA-LA (p=0.034). After 11 weeks in vivo PGSA-HA mass loss wassignificantly higher than PGSA-PEG at 12 weeks in vivo (p<0.001).

PGS showed constant water content over time, whereas the water contentof all photocured elastomers rose initially and then declined (see FIG.16B). The time to peak water content was observed to follow the orderPGSA-LA<PGSA-HA<PGSA-PEG.

The sol content (macromers not connected to the backbone of thematerial) of PGSA-HA and PGSA-PEG, were comparable to the sol content ofPGS (p>0.05) (see FIG. 16C). The average sol content of PGSA-LA overtime was significantly higher than that of the other elastomers(p<0.001).

The thickness of the implanted discs of PGS and PGSA-LA (see FIG. 16D)decreased rapidly. At week 7, the thickness of PGSA-HA discs wassignificantly lower than the initial thickness of the implants (p<0.01).The thickness of PGSA-PEG discs was essentially unchanged over time(p>0.05). These findings correlate with the patterns of dry massremaining (see FIG. 16A).

The mechanical strength of PGSA-LA and PGS decrease (data is presentedin FIG. 17): at 3 weeks in vivo PGS and PGSA has lost 40%, while bothPGSA-HA and PGSA-PEG lost only 13% of its original strength (p<0.004).PGSA-HA at 11 weeks in vivo lost >90% of its original strength whilePGSA-PEG only lost 40% of its original strength at 12 weeks in vivo(p<0.001). Similar to the thickness of the polymeric discs, themechanical strength over time in vivo (see FIG. 17) approximatelyfollows the same patterns as the mass remaining (see FIG. 16A).

SEM analysis of the cross-section (data is presented in FIGS. 18A-H) ofPGS, PGSA-LA and PGSA-HA indicates that the structural integrity ismaintained, while up to 80% of the material is degraded. In contrast,PGSA-PEG shows formation of pores within the bulk of the material after9 weeks in vivo. SEM analysis of the surface of PGS, PGSA-LA, PGSA-HAand PGS-PEG shows a comparable surface topography (data is presented inFIGS. 19A-D).

Degradation of PGS (the positive control for a surface eroding polymer)showed a linear decrease in mass remaining (see FIG. 16A), a constantand low water content of the explants over time (see FIG. 16B), a lineardecrease of the discs thickness (see FIG. 16D) and a linear mechanicalstrength loss over time (see FIG. 17). Due to the relatively fastdegradation at the surface the mass loss is linear and the sol contentand water content remains low and constant. The decrease in mechanicalstrength (see FIG. 17) is believed to be due to hydrolysis where bondsare cleaved within the bulk. These results, together with the slow invitro degradation in PBS suggest that the degradation mechanism of PGSin vivo is predominantly enzymatic surface degradation. However, duringenzymatic surface degradation, it is believed bonds are being cleaveddue to hydrolysis in the bulk of the material.

For the photocured elastomers, incorporation of acrylate groups in thePGS pre-polymer and subsequent photocuring decreased the degradationrate in vivo (see FIG. 16A). Although, the crosslinking density ofPGSA-LA is lower than PGS (see Table 1), the degradation of PGSA-LA isslower. It is believed, without being held to theory, that this is dueat least in part to the methylene cross-links in PGSA degrading slowerthan the original PGS cross-links. The methylene cross-links wasobserved to affect the degradation profile; PGSA-LA shows a linear massloss over time, while PGSA-HA shows an initial 5% mass loss in the first5 weeks, followed by an accelerated linear mass loss (see FIGS. 16A-D).

The degradation mechanism of these photocured polymers is not obvious.PGSA-LA shows a typical degradation profile for surface degradation:structural integrity during degradation (see FIGS. 18B and 18F), linearmass loss and linear size loss over time (see FIGS. 16A and 16D).However, the water content and sol content changes drastically over time(see FIGS. 16B and 16C). Therefore, it is believed, without being heldto theory, that the degradation of PGSA-LA is due to both surface andbulk degradation.

PGSA-HA showed a bulk degradation profile with at first an increasingwater content followed by an accelerated mass loss in time. Themechanical properties of the PGSA-HA samples were 77% of their originalstrength at 5 weeks, while the mass loss was only 5%. However, thestructural integrity of the PGSA-HA discs and the sol content over timedoes not point towards bulk degradation (see FIGS. 16C, 18C and 18H). Itis believed, without being held to theory, that he initial 5% mass lossof PGSA-HA (first 5 weeks) is due largely to hydrolysis in the bulk,decreasing its crosslink density (and mechanical strength) andincreasing the water content of the PGSA-HA explants. The change inwater content and possibly the exposure of the methylene cross-links,after 5 weeks, accelerates the degradation of the photocured cross-linkson the surface.

The different profile observed for PGSA-LA and PGSA-HA in the first 5weeks is comparable to what was observed in vitro. Initially PGSA-LA isdegraded by cholesterol esterase, while PGSA-HA is not. This suggeststhat the degradation of the methylene cross-links on the surface(PGSA-LA and PGSA-HA after 5 weeks) is likely due to enzymes, while thedegradation in the bulk of the material for PGSA-LA and PGSA-HA is dueto hydrolysis. Which is supported by both the in vitro and in vivoenzymatic degradation of polyesters from the surface. In addition, invitro and in vivo hydrolytic degradation is observed in the bulk and atthe surface.

The copolymerization of PEG-diacrylate with PGSA-LA results in longmethylene cross-links (due to acrylate groups) and low molecular PEGchains in the biomaterial's network. The incorporation of the PEG chainsin the biomaterial's network decreases the degradation ratesubstantially (see FIG. 16A). Similar to PGSA-HA, PGSA-PEG shows aninitial slow mass loss and an increase in water content over time.Although, the water content of PGSA-PEG has reached its maximum after 9weeks (see FIG. 16B) an accelerated mass loss has not yet been observedafter 12 weeks in vivo (see FIG. 16A). The degradation observed forPGSA-PEG in vivo up to 12 weeks is believed to be largely due tohydrolytic bulk degradation. Degradation of PGSA-PEG was 20% after 12weeks in vivo while for PGSA-HA, with the same cross-linking density,the degradation was more than 50%. As can be seen, these embodimentsprovided a decrease in the degradation rate of PGSA independent of thecross-linking density. SEM images of the cross-section of PGSA-PEGexplants show pore formation in the explants after 9 weeks in vivo (seeFIGS. 18D and 18H), which supports the bulk degradation mechanism. Thesol content of PGSA-PEG was observed to be not as high as the bulkeroding PGSA-LA. However, this could be due to the greater solubility ofmacromers which include a short PEG chain, making it difficult tocompare the sol content of PGSA-PEG and PGSA.

The degradation rate of the implanted slabs was observed to be dependenton the types of cross-links in the material. An increase in thephoto-induced methylene cross-links was observed to result in a decreasein degradation rate. Compared to PGS, the degradation rate of PGSA isslower. Incorporation of PEG has a greater effect; and facilitatesdecreasing the degradation rate of PGSA substantially independently ofthe crosslinking density.

The degradation mechanism of the implanted PGSA slabs was also affected.PGS was observe to be degraded by surface degradation. Incorporation ofacrylate groups into the PGS backbone was observed to result in a changein the degradation mechanism. Both PGSA-LA and PGSA-HA showed bulkdegradation possibly by hydrolysis and a relatively fast surfacedegradation believed to be due to enzymes. However for PGSA-HA, surfacedegradation was observed after 5 weeks, whereas PGSA-LA showed both bulkand surface degradation substantially continuously. Incorporation of PEGchains in the biomaterial resulted in predominantly bulk degradation byhydrolysis up to 12 weeks in vivo.

In Vivo Biocompatibility

On dissection, discs of the materials were encased in a translucenttissue capsule, with some vascularity. The surrounding tissues wereotherwise normal in appearance, allowing for changes attributable to theimplantation process at the earliest time points. The polymeric diskswere easily separated from the capsule at all time points. To visualinspection, they were smooth-surfaced initially, then becameprogressively rougher over time (see FIGS. 18A-H), with a time coursethat paralleled the mass loss over time (see FIG. 16A). Histologicalassessment of the cross-linked materials and surrounding tissues showedcomparable levels of mild inflammation surrounding all discs thateventually transitioned into a fibrous capsule over time. Fibroblastswere mostly present in fibrous capsule, and no cell in growth in thepolymeric discs was observed. The tissues surrounding all the polymericdiscs showed no observable injury. Inflammatory cells were commonlyfound at the interface between the tissues and the degrading polymer.More specifically, when comparing PGS with PGSA-HA (see FIGS. 20A-F),PGS showed a higher inflammatory activity at week 1 and week 3 thanPGSA-HA, corresponding to the high mass loss of PGS and the initial lowmass loss of PGSA-HA. However, after 5 weeks, PGSA-HA showed a similarinflammatory response compared to PGS at week 1 and 3. PGSA-LA showed agreater inflammatory activity from week 1, compared to PGSA-PEG (seeFIGS. 21A-F) inflammatory cells were predominantly located between thefibrous capsule and tissue polymer interface for PGS, PGSA-LA andPGSA-HA (after week 5). While for PGSA-HA (before week 7) and PGSA-PEGthe fibrous capsule was directly on the tissue polymer interface (seeFIGS. 20A-F, 21A-F). This indicates that the presence of inflammatorycells was associated with the degradation of PGS, PGSA-LA and PGSA-HA(after 5 weeks). As it is believed that inflammatory cells areassociated with a high activity of cholesterol esterase, these resultssupport the belief that the high mass loss over time in vivo is due toenzymatic degradation.

All literature and similar material cited in this application,including, but not limited to, patents, patent applications, articles,books, treatises, and web pages, regardless of the format of suchliterature and similar materials, are expressly incorporated byreference in their entirety. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described inany way.

While the present inventions have been described in conjunction withvarious embodiments and examples, it is not intended that the presentinventions be limited to such embodiments or examples. On the contrary,the present inventions encompass various alternatives, modifications,and equivalents, as will be appreciated by those of skill in the art.

While the present inventions have been particularly shown and describedwith reference to specific illustrative embodiments, it should beunderstood that various changes in form and detail may be made withoutdeparting from the spirit and scope of the present inventions.Therefore, all embodiments that come within the scope and spirit of thepresent inventions, and equivalents thereto, are claimed. The claims,descriptions and diagrams of the methods, systems, and assays of thepresent inventions should not be read as limited to the described orderof elements unless stated to that effect.

What is claimed is:
 1. An elastomeric composition comprising across-linked polyester, the cross-linked polyester comprising: apolymeric unit of the general formula (-A-B—)_(n) cross-linked betweenat least a portion of the A components of the polyester, at least aportion of the cross-links forming a dioic acid ester; wherein, Arepresents a substituted or unsubstituted ester, B represents asubstituted or unsubstituted acid ester comprising at least two acidester functionalities; and n represents an integer greater than
 1. 2.The composition of claim 1, wherein the cross-linked polyester comprisesa portion that can be represented by the general formula (I)

wherein m, n, p, q, and v each independently represent an integergreater than
 1. 3. The composition of claim 2, wherein p=8, q=8 and v=4.4. The composition of claim 1, wherein the average ratio of the numberof cross-links to the number of (-A-B—)_(n), polymeric units is lessthan about 0.4.
 5. The composition of claim 1, wherein the average ratioof the number of cross-links to the number of (-A-B—)_(n), polymericunits is greater than about 0.5.
 6. The composition of claim 1, whereinthe at least a portion of the cross-links forming a dioic acid estercomprise one or more substituted or unsubstituted alkylesterfunctionalities.
 7. The composition of claim 1, wherein the at least aportion of the cross-links forming a dioic acid ester comprise one ormore substituted or unsubstituted carbonic acid alkylesterfunctionalities.
 8. The composition of claim 1, wherein the cross-linkedpolyester comprises a polymeric unit of the general formula (-A-B—)_(n)cross-linked to a substituted or unsubstituted alkane through at least aportion of the A components of the polyester, at least a portion of thecross-links forming an acid ester; wherein, A represents a substitutedor unsubstituted ester, B represents a substituted or unsubstituted acidester comprising at least two acid ester functionalities; and nrepresents an integer greater than
 1. 9. A biodegradable material formedfrom the composition of claim 1, the material having a tensile Young'smodulus less than about 1.5 MPa when measured according to ASTM standardD412-98a.
 10. A biodegradable material formed from the composition ofclaim 1, the material having a tensile Young's modulus greater thanabout 0.05 MPa and an elongation of greater than about 45%, both whenmeasured according to ASTM standard D412-98a.
 11. A biodegradablematerial formed from the composition of claim 1, the material having aYoung's modulus in the range between about 0.4 MPa and about 0.55 MPawhen measured according to ASTM standard D412-98a.
 12. A biodegradablematerial formed from the composition of claim 1, the material having amaximum elongation greater than about 170%.
 13. A biodegradable materialformed from the composition of claim 1, wherein the biodegradablematerial is one or more of non-toxic to humans, biocompatible andbioabsorbable.
 14. An elastomeric composition comprising a cross-linkedpolyester, the cross-linked polyester comprising: a polymeric unit ofthe general formula (-A-B—)_(n) cross-linked between at least a portionof the A components of the polyester, the cross-link forming a linkcomprising at least a portion of the general formula -(D)_(k)-C—;wherein A represents a substituted or unsubstituted ester, B representsa substituted or unsubstituted acid ester comprising at least two acidester functionalities; C represents a substituted or unsubstituted dioicacid ester; D represents one or more of a substituted or unsubstitutedester; n represents an integer greater than 1; and k represents aninteger greater than
 0. 15. The composition of claim 14, wherein thecross-linked polyester comprises at least a portion that can berepresented by the general formula (II)

wherein m, n, p, q, and v each independently represent an integergreater than 1, and k represents an integer greater than
 0. 16. Thecomposition of claim 15, wherein p=8, q=8 and v=4.
 17. The compositionof claim 14, wherein the average ratio of the number of cross-links tothe number of (-A-B—)_(n), polymeric units is less than about 0.4. 18.The composition of claim 14, wherein the average ratio of the number ofcross-links to the number of (-A-B—)_(n) polymeric units is greater thanabout 0.5.
 19. The composition of claim 14, wherein the cross-linkedpolyester comprises a polymeric unit of the general formula (-A-B—)_(n)cross-linked to a substituted or unsubstituted alkane through at least aportion of the A components of the polyester, at least a portion of thecross-links forming an acid ester; wherein, A represents a substitutedor unsubstituted ester, B represents a substituted or unsubstituted acidester comprising at least two acid ester functionalities; and nrepresents an integer greater than
 1. 20. A biodegradable materialformed from the composition of claim 14, the material having a tensileYoung's modulus less than about 17 MPa when measured according to ASTMstandard D412-98a.
 21. A biodegradable material formed from thecomposition of claim 14, the material having a tensile Young's modulusgreater than about 0.6 MPa and an elongation of greater than about 20%,both when measured according to ASTM standard D412-98a.
 22. Abiodegradable material formed from the composition of claim 14, thematerial having a tensile Young's modulus greater than about 0.25 MPawhen measured according to ASTM standard D412-98a and a swelling inwater of greater than about 1%.
 23. A biodegradable material formed fromthe composition of claim 14, the material having a tensile Young'smodulus greater than about 0.25 MPa when measured according to ASTMstandard D412-98a and a swelling in water of greater than about 40%. 24.A biodegradable material formed from the composition of claim 14, thematerial having a Young's modulus in the range between about 0.4 MPa andabout 0.55 MPa when measured according to ASTM standard D412-98a.
 25. Abiodegradable material formed from the composition of claim 14, thematerial having a maximum elongation greater than about 60%.
 26. Abiodegradable material formed from the composition of claim 14, whereinthe biodegradable material is one or more of: non-toxic to humans,biocompatible and bioabsorbable.
 27. An elastomeric biodegradablematerial formed from a cross-linked polyester, the elastomericbiodegradable material having a degradation rate that is substantiallynon-monotonic as a function of overall cross-link density.
 28. Theelastomeric biodegradable material of claim 27, wherein the cross-linkedelastomeric polyester comprises: a polymeric unit of the general formula(-A-B—)_(n) cross-linked between at least a portion of the A componentsof the polyester, the cross-link forming a link comprising at least aportion of the general formula -(D)_(k)-C—; wherein A represents asubstituted or unsubstituted ester, B represents a substituted orunsubstituted acid ester comprising at least two acid esterfunctionalities; C represents a substituted or unsubstituted dioic acidester; D represents one or more of a substituted or unsubstituted ester;n represents an integer greater than 1; and k represents an integergreater than
 0. 29. An elastomeric biodegradable material of claim 27,wherein the degradation rate is the in vivo degradation rate
 30. Anelastomeric biodegradable material of claim 27, wherein the degradationrate is the in vitro degradation rate in phosphate buffer saline (PBS),or in acidic or alkaline conditions.
 31. A method for forming abiodegradable elastomeric material, comprising the steps of: (a)reacting a first component comprising two or more functionalities of thegeneral formula —OR, where R of each group is independently hydrogen oralkyl, with a second component comprising two or more acid esterfunctionalities to form a mixture of pre-polymers having a molecularweight in the range between about 300 Da and about 75,000 Da; (b)reacting the mixture of pre-polymers with an acrylate to form a mixtureof acrylated pre-polymers; and (c) irradiating the acrylated pre-polymermixture with ultraviolet light to cross-link at least a portion of theacrylated pre-polymers and form a biodegradable elastomeric material;wherein the pre-polymer mixture is not heated above about 45° C. duringirradiation.
 32. The method of claim 31, wherein the acrylate comprisesone or more of

wherein, R₁ represents methyl or hydrogen; R₂, R₂′, and R₂″ representindependently alkyl, aryl, heterocycles, cycloalkyl, aromaticheterocycles, multicycloalkyl, hydroxyl, ester, ether, halide,carboxylic acid, amino, alkylamino, dialkylamino, trialkylamino, amido,carbamoyl thioether, thiol, alkoxy, or ureido groups, and branched andsubstituted versions thereof.
 33. The method of claim 31, wherein thepre-polymer mixture is not heated above about 25° C. during irradiation.34. The method of claim 31, wherein step (b) comprises adding to thereaction one or more of an acrylated dextran, acrylated hyaluronic acid,acrylated chitosan, and acrylated poly(ethylene glycol).
 35. A methodfor forming a biodegradable elastomeric material, comprising the stepsof: (a) providing a solution comprising: a first component comprisingtwo or more functionalities of the general formula —OR, where R of eachgroup is independently hydrogen or alkyl; and a second componentcomprising two or more acid ester functionalities; (b) forming areaction mixture by adding diisopropyl azodicarboxylate andtriphenylphosphine to the pre-polymer solution to crosslink at least aportion of the pre-polymers to form a biodegradable elastomericmaterial; wherein, the reaction mixture is not heated above about 25° C.36. The method of claim 35, wherein the step of forming a reactionmixture comprises adding a mono-acid to provide an ester linked sidechain in the biodegradable elastomeric material.
 37. The method of claim35, wherein the step of forming a reaction mixture comprises adding amono-alcohol to provide an ether linked side chain in the biodegradableelastomeric material.
 38. The method of claim 35, wherein the secondcomponent is a substituted or unsubstituted dioic acid ester.
 39. Themethod of claim 35, wherein the second component of the pre-polymercomprises an amino ester functionality and the biodegradable elastomericmaterial comprises a poly-β-amino ester polymer.
 40. A method forforming a biodegradable elastomeric material, comprising the steps of:(a) providing a solution comprising: a first component comprising two ormore functionalities of the general formula —OR, where R of each groupis independently hydrogen or alkyl; and a second component comprisingtwo or more acid ester functionalities; (b) crosslinking at least aportion of the pre-polymers by thermal initiated polymerization using athermal initiator, by redox-pair initiated polymerization, or both,wherein the crosslinking reaction is conducted at a temperature of lessthan about 25° C.
 41. A method for forming a biodegradable elastomericmaterial, comprising the steps of: (a) providing a solution comprising:a first component comprising two or more functionalities of the generalformula —OR, where R of each group is independently hydrogen or alkyl;and a second component comprising two or more acid esterfunctionalities; (b) crosslinking at least a portion of the pre-polymerswith a Michael-type addition reaction using a bifunctional sulfhydrylcompound, wherein the crosslinking reaction is conducted at atemperature of less than about 25° C.
 42. A method of forming a medicaldevice comprising the steps of: injecting an acrylated pre-polymer ofclaim 31 at a site where the medical device is desired; and irradiatingthe injected acrylated pre-polymer with ultraviolet light to form amedical device.
 43. The method of claim 42, wherein the medical deviceprovides delivery of a bioactive agent over time.
 44. An elasticbiodegradable material formed from a composition of claim 1 or claim 14,further comprising one or more of a growth factor, cell adhesionsequence, polynucleotide, polysaccharide, polypeptide, an extracellularmatrix component, and combinations thereof.
 45. An elastic biodegradablematerial formed from a composition of claim 1 or claim 14, wherein theelastic biodegradable material is seeded with one or more connectivetissue cells, organ cells, muscle cells, nerve cells, and combinationsthereof.
 46. An elastic biodegradable material formed from a compositionof claim 1 or claim 14, wherein the elastic biodegradable material isseeded with one or more tenocytes, fibroblasts, ligament cells,endothelial cells, lung cells, epithelial cells, smooth muscle cells,cardiac muscle cells, skeletal muscle cells, islet cells, nerve cells,hepatocytes, kidney cells, bladder cells, urothelial cells,chondrocytes, and bone-forming cells.
 47. An elastic biodegradablematerial formed from a composition of claim 1 or claim 14, wherein achromophore is covalently linked to the cross-linked polyester.
 48. Theelastic biodegradable material of claim 45, wherein a receptor iscovalently linked to the chromophore or interposed between thechromophore and the cross-linked polyester.
 49. An elastic biodegradablematerial formed from a composition of claim 1 or claim 14, wherein theelastic biodegradable material is porous.
 50. An elastic biodegradablematerial formed from a composition of claim 1 or claim 14, wherein thecomposition comprises a porogen.
 51. An elastic biodegradable materialformed from a composition of claim 1 or claim 14, wherein thecomposition comprises a bioactive agent.
 52. An elastic biodegradablematerial formed from a composition of claim 1 or claim 14, wherein theelastic biodegradable material is in the form of a particle, tube,sphere, strand, coiled strand, capillary network, film, fiber, mesh, orsheet.